Subscribe to RSS
Download PDF
DOI: 10.1055/s-0046-1816066
Effect of Natural Products in the Prevention and Treatment of Colorectal Cancer
Authors
Abstract
Colorectal cancer (CRC) is recognized as a significant and emerging global public health concern. The increasing incidence and associated mortality rates are attributable to a complex interplay of genetic predisposition, adverse environmental exposures, and modifiable lifestyle factors. Current therapies, e.g., chemotherapy and surgery, do not demonstrate satisfactory clinical outcomes and are often associated with undesired side effects. This has led to the search for alternative or adjunctive treatments. Natural products derived from microorganisms, marine organisms, and plants comprise a wealth of bioactive compounds that have long been recognized for their beneficial and safe profiles. These natural products provide attractive adjuvant therapies for the prevention and therapy of CRC.
This review highlights the anti-CRC activity of natural compounds such as resveratrol, curcumin, and quercetin, along with corresponding molecular mechanisms associated with their anti-CRC actions: modulation of inflammation, oxidative stress, cell proliferation, and apoptosis. They may also enhance the efficacy of conventional chemotherapeutic agents and reduce their toxicities by inhibiting signaling pathways, including nuclear factor kappa B (NF-κB), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), and Wnt signaling pathway and β-catenin (Wnt/β-catenin). Unfortunately, in contrast to a great many promising pre-clinical data, there is still little validation. More research, particularly on bioavailability and balance of dose and long-term safety, is required for these compounds. In conclusion, natural products show great promise as chemopreventive and therapeutic agents against CRC. Their integration into pharmacology, oncology, and nanomedicine should be continuously promoted to maximize the potential of these agents in a personalized medicine setting.
Introduction
Colorectal cancer (CRC) represents the third most common cancer in the world, and is known to be affected by genetic, environmental, and lifestyle issues.[1] CRC is more frequent in Europe, North America, and Australia than in West Africa. Screening is one of the most efficient strategies, and is effective in significantly reducing the risk of mortality, offering less invasive treatment procedures, better prognosis, and a cost-effective manner of addressing CRC.[2]
CRC is the third most common cancer worldwide, following lung and breast (in women) or prostate (in men) cancer. Worldwide, in 2022, there were about two million new CRC cases, including approximately 900,000 deaths due to CRC in the same year. CRC is responsible for 9% of all cancers worldwide.[3]
Genetic mutations are a significant risk factor for CRC. Lifestyle factors, obesity, inactivity, and substance use, are also risk factors for CRC.[4] Additionally, nutritional factors, including red meat (particularly processed red meat), saturated fat-rich food, as well as alcohol consumption and smoking, are the leading risk factors for CRC.[5] [6] [7] Preventative strategies include dietary modification, encouraging physical activity, and public education campaigns.[4]
Despite the development of therapies targeting CRC, approaches are constrained with respect to efficacy, safety, and long-term outcome. Conventional therapies, including surgery, chemotherapy, radiotherapy, and immunotherapy, are constrained by tumor heterogeneity, drug resistance, and factors relating to the patients.[8] CRC has a complex molecular and genetic landscape that encompasses differing tumor subtypes and microenvironments, which ultimately render standard treatments ineffective, since uniform approaches do not account for the specific biological properties.[9] Resistance to cytotoxic compounds generally develops during treatment and is mediated by increased deoxyribonucleic acid (DNA) repair, efflux pump activity, and altered apoptotic pathways, leading to therapy resistance.[10]
Due to these limitations, other therapeutic options, especially natural agents, are now being studied. These molecules, also known as natural-product compounds, obtained from several sources (e.g., plants, marine organisms, and microorganisms) have promising effects in modulating the molecular pathways that are implicated in cancer development. A large number of bioactive compounds have been used for their aroma, flavor, and medicinal applications. In addition to the discovery of novel pharmaceutical molecules, researchers are constantly trying to identify other natural sources for new therapeutic agents.[11] Nutritional elements like fruits and vegetables that are rich in bioavailable compounds such as phenols, carotenoids, and glucosinolates have repeatedly been shown to reduce the risk of developing CRC.[12] [13] For example, curcumin decreases the proliferation and increases apoptosis of cancer cells, while resveratrol controls apoptosis and the cell cycle, suppressing tumor growth. Omega-3 fatty acids also have a role in controlling anti-inflammatory pathways in cancer progression.[13]
The objective of this review is to provide an overview of the available evidence on the antitumor activities exerted by natural products in CRC. We review the source, role, pharmacokinetics, pharmacodynamics, and mechanism of action of natural products (such as resveratrol, curcumin, and quercetin) in vivo, in vitro, and in clinical trials. We end by acknowledging the current evidence gap and the importance of ongoing clinical trials to confirm these attractive compounds for use in CRC treatment.
Materials and Methods
To investigate the possible role of natural products in the prevention and treatment of CRC, a systematic review of the existing literature was conducted. The following methodology was employed.
Databases Searched
A comprehensive search was performed in relevant electronic databases (PubMed, Scopus, Web of Science, and Google Scholar). These databases were chosen because of the extensive coverage of cancer-related and natural compound research. Such a search was conducted to cover the possible molecular mechanisms of CRC, as well as the therapeutic roles of natural products (bioavailability, pharmacokinetics, pharmacodynamics, and adverse effects).
Date Range
This review included studies published from January 2003 to October 2025. The recent 15 years were used as the time parameter to highlight discoveries and information on how natural products regulate CRC progression.
Keywords
The search strategy consisted of using specific keywords such as “Colorectal cancer,” “search on natural products,” “search on natural products for colorectal cancer,” phytochemicals, herbal medicine, anticancer, resveratrol, curcumin, with searching operators and or/NOT to combine the keywords like (chemoprevention OR therapeutic agents). AND and OR operators were employed to merge these latter terms for an extensive retrieval of pertinent studies.
Inclusion Criteria
The eligible studies were pre-clinical (in vitro and in vivo) or clinical trials, and reviews regarding natural products applied for the prevention/treatment of CRC published in English. Valid studies including the mechanisms, signaling pathways, anti-inflammatory effects, apoptosis induction, and regulation of oxidative stress in CRC were submitted for inclusion.
Exclusion Criteria
We excluded studies that were not about CRC or natural products, did not contain enough data, had confusing methodologies, or had insufficient data, and non-English language.
Data Extraction
Information was collected on study characteristics (design, sample size), natural products investigated, treatment protocols, and molecular endpoints. We focused on bioactive compounds and their role in CRC pathways, summing up useful molecules. Results underscore the need to combine natural therapies with standard-of-care treatments as part of a regimen for improved CRC outcomes.
Molecular Mechanisms of Colorectal Carcinogenesis
Colorectal carcinogenesis results from genetic and epigenetic changes that transform normal colonic epithelium into malignant cells. Key mutations occur in tumor suppressor genes and DNA repair genes.[14] CRC exists in three primary forms: inherited (such as in familial adenomatous polyposis coli [APC] and Lynch syndrome), sporadic (accounting approximately 70–80% of all CRC), and familial (without identifiable genetic mutations). CRC development follows three pathways: chromosomal instability (gene mutations include APC, Kirsten rat sarcoma viral oncogene homolog [KRAS], and tumor protein 53 [TP53]), microsatellite instability (defects in DNA mismatch repair genes, e.g., MutL homolog 1 [MLH1], MSH2, MSH6, PMS2), and the CpG island methylator phenotype pathway.[15] [16]
Tissue homeostasis depends on controlled cell division and apoptosis, excluding stem cells. Tumors arise from uncontrolled division and insufficient self-elimination. Three gene groups contribute to cancer deregulation: proto-oncogenes, tumor suppressor genes, and DNA stability genes. A single genetic change alone does not cause tumors or metastasis. Most tumors exhibit diverse cell populations with varying abilities to repopulate or metastasize. Malignant progression from normal tissue to tumor and metastasis occurs in distinct steps over time,[17] as shown in [Fig. 1].
Genetic Mutations
CRC, one of the most frequent and serious cancers worldwide, is predominantly caused by the introduction of sporadic gene mutations that interrupt homeostatic processes. Significant mutations in the APC, KRAS, and TP53 genes are critical for tumorigenesis. The tumor suppressor gene APC controls the Wnt (Wingless-related integration site) pathway for differentiation and cell proliferation.[18]
Mutations at APC often generate an abnormal protein that no longer destroys β-catenin, and β-catenin becomes very stable, resulting in activation of Wnt target genes responsible for unchecked cell division.[19]
This mutation is commonly encountered in sporadic colorectal carcinoma and is pathognomonic for familial adenomatous polyposis, underscoring its significance in carcinogenesis. In contrast, KRAS, an oncogene, is commonly point mutated in CRC, which results in the continuous activation of the Ras signaling pathway, leading to cell survival and proliferation. The presence of the mutation KRAS keeps the signaling path active and is responsible for a bad prognosis and treatment.[19] Likewise, alterations in the tumor suppressor TP53 exacerbate CRC, as expression of p53 protein (encoded by TP53) controls cellular responses to DNA damage. p53 mutations are often inactivating, such that mutant p53 is unable to suppress genetically unstable cells from proliferating, and tumors can progress.[20]
The complex functions of these mutations bring new dimensions to CRC oncogenesis. The APC, KRAS, and TP53 mutations emphasize the complex nature of this disease and remain critical therapeutic targets, fueling the ramp-up in targeted therapy strategies to combat these genetic hurdles and ultimately leading to more personalized cancer treatment[18] ([Fig. 1]).
Inflammatory Pathways
In the pathogenesis of CRC, inflammatory pathways have been found to play an important role, mainly mediated by cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB). COX-2, which is often overexpressed in CRC, metabolizes arachidonic acid to prostaglandins, particularly E2. This metabolite modulates the tumor microenvironment through induction of angiogenesis, apoptosis inhibition, cell growth, and invasion promotion. Higher levels of COX-2 are associated with aggressive tumor behavior and poorer outcome, rendering it a potentially useful therapeutic target.[21]
CRC inflammatory reaction is also mainly mediated by the pathway of NF-κB signaling. It functions as a transcription factor that regulates genes associated with cell survival and immune function. In response to a stimulus, it translocates into the nucleus where it binds DNA and activates gene transcription, leading to pro-survival and pro-inflammatory responses. The pro-carcinogenic inflammatory microenvironment is a product of chronic activation in cancer cells, and natural products have the potential to modulate by attenuating this pathway,[22] as demonstrated in [Fig. 1].
Epigenetic Regulation Mechanisms
This type of modification, methylation of DNA, and changes in histone cause a great change in gene expression without changing the DNA sequence. Their ability to modulate gene expression is critical in the advancement and growth of CRC.[23] For example, in DNA methylation, methyl groups are added to cytosine nucleotides within promoters or other genes, and upregulation of this modification is frequently associated with gene silencing. In CRC, tumor suppressor genes are commonly hypermethylated, which promotes cancer progression.[24] In addition, non-coding ribonucleic acids (RNAs) such as long non-coding RNAs (lncRNAs) and microRNAs are involved in the pathophysiology of CRC. Their abnormal expression is correlated with tumorigenesis, and also impacts the cell cycle, apoptosis, and metastasis fate[25] ([Fig. 1]).
Tumor Microenvironment and Oxidative Stress
The tumor microenvironment (TME) plays a crucial role in the development of CRC via cellular and noncellular components (immune cells, endothelial cells, and fibroblasts) crosstalk. Recent evidence emphasizes the strong effect of oxidative stress on the TME, affecting tumor cell survival and proliferation, as well as affecting stromal and immune cells.[26]
When the ideal equilibrium between antioxidant and reactive oxygen species (ROS) production is disrupted, oxidative stress evolves. In CRC's TME, the increased content of ROS can lead either to DNA damage and mutagenesis or to triggering pathways beneficial for tumor expansion. In addition, oxidative stress also deregulates the polarization of immune cells, especially macrophages, for their orientation toward tumor promotion and inhibition of anti-tumor responses. This interaction helps tumors evade immune detection,[27] as shown in [Fig. 1].[28]
Mechanisms of Action of Natural Products in CRC
CRC presents significant health challenges due to its complex etiology and resistance to therapies. Molecular profiling has revealed new therapeutic opportunities through natural-origin compounds that regulate key CRC-related signaling pathways.[29] These natural products, such as flavonoids, resveratrol, curcumin, alkaloids, and catechins, target multiple pathways, including PI3K/Akt/mTOR and Wnt/β-catenin, to inhibit cancer cell growth, induce apoptosis, and reduce chronic inflammation. Additionally, catechins neutralize free radicals, preventing oxidative DNA damage and CRC progression.[30] [31] [32] [33] The broad spectrum of action of these compounds suggests their potential as adjuncts to chemotherapy, enhancing efficacy without harming patient health. Further investigation into these mechanisms could advance CRC treatment,[34] as shown in [Fig. 2].
Antioxidant and Anti-inflammatory Effects
Phytocompounds demonstrate therapeutic potential in CRC treatment through antioxidative and anti-inflammatory mechanisms. Chronic inflammation releases cytokines and enzymes that promote cancer growth, while radioactive species (ROS) destabilize DNA, initiating carcinogenesis. These pathways can be modulated by natural compounds derived from various sources.[35]
Natural products scavenge ROS via antioxidant activity, with polyphenols, flavonoids, and carotenoids from fruits and herbs neutralizing free radicals and stimulating protective enzymes. Curcumin reduces ROS levels and modulates enzyme activity, while resveratrol sensitizes Nrf2, regulating antioxidant responses. These effects mitigate oxidative stress and DNA mutations in CRC.[36] Furthermore, natural products exert anti-inflammatory effects by inhibiting NF-κB, a key driver of cytokine production and inflammation-mediated proliferation. Agents such as epigallocatechin gallate (EGCG), gingerols, and omega-3 fatty acids suppress NF-κB activation, reducing inflammatory signaling, angiogenesis, and tumor progression. These antioxidant and anti-inflammatory actions enhance therapeutic responsiveness and promote apoptosis induction,[37] as shown in [Fig. 2].
Modulation of Signaling Pathways
In CRC, the dysregulation of key intracellular signaling pathways drives the transition from normal epithelium to malignant adenocarcinoma. Several intracellular pathways, particularly Wnt/β-catenin, PI3K/Akt/mTOR, and mitogen-activated protein kinase (MAPK), play central roles in CRC development. Natural compounds modulate these nodes and disrupt cancer-promoting signaling: Wnt/β-catenin: Mutations affecting APC or β-catenin drive uncontrolled proliferation. Curcumin suppresses β-catenin transcriptional activity, and resveratrol promotes its degradation, limiting aggressive tumor growth.[38] [39] Also, PI3K/Akt/mTOR pathway mutations promote survival, proliferation, and chemoresistance. Flavonoids such as quercetin and resveratrol inhibit PI3K/Akt signaling and mTOR genes, which sensitize cancer cells to apoptosis. The MAPK/extracellular signal-regulated kinase (ERK) pathway relays signals from the cell surface (like EGFR) to the nucleus. Chronic activation leads to uncontrolled proliferation and metastasis. The MAPK pathway functions in gene expression and cellular response to stimuli via ERK, JNK, and p38. MAPK regulates cell proliferation and stress responses. Through coordinated suppression of these pathways, natural products limit tumor growth and enhance treatment efficacy. Compounds such as EGCG and quercetin inhibit ERK activation, thereby reducing proliferation and increasing cancer cell death.[30] [40] Berberine enhances chemotherapy response by blocking this pathway and reversing chemoresistance,[41] as demonstrated in [Fig. 2].
Enhancement of Apoptosis and Cell Cycle Arrest
Apoptotic signaling is often disrupted in CRC, enabling uncontrolled cell survival. Natural products restore apoptotic balance by modulating critical regulatory proteins, including the activation of caspases (especially caspase-3, -8, and 9), Bcl-2-associated X protein (Bax)/B cell lymphoma (Bcl-2) ratio, and activating mitochondrial and death receptor apoptotic pathways. Curcumin and resveratrol activate the intrinsic apoptosis pathway, upregulating pro-apoptotic proteins and triggering caspase activation. They may also stimulate death receptor–mediated apoptosis, further enhancing tumor cell clearance.[42] [43]
These compounds additionally induce cell cycle arrest, particularly at the G1/S and G2/M checkpoints. EGCG inhibits cyclin D1, preventing G1–S progression, while flavonoids like quercetin suppress cyclin-dependent kinase (CDK) activity, allowing time for DNA repair or promoting apoptosis when damage is irreparable.[44] [45] Together, apoptosis induction and mitotic arrest contribute to the cytostatic and cytotoxic effects of natural products on CRC cells.[46] [47] Reactivating tumor suppressor genes is a critical strategy in treating CRC, as these “molecular brakes” are often silenced by mutations or epigenetic changes. Some natural compounds increase p53 levels by preventing its proteasomal degradation. This leads to an increase in p21, which binds to CDK complexes to arrest the cell cycle at the G0/G1 phase,[48] as shown in [Fig. 2].
Inhibition of Angiogenesis and Epigenetic Regulation
Natural products can suppress angiogenesis (formation of new blood vessels), which is essential for tumor growth and metastasis. A key pathway is vascular endothelial growth factor (VEGF) and nuclear factor-kappa B (NF-κB). In CRC, constitutive NF-κB activation drives tumorigenesis by promoting the production of pro-inflammatory cytokines and anti-apoptotic proteins signaling, which decreases blood vessel density in HCT116 xenografts, resulting in reduced inflammation and increased apoptosis,[49] and hypoxia-inducible factor (HIF-1α) inhibits cell migration and tube formation, and/or promotes proteasomal degradation of HIF-1α. Resveratrol inhibits VEGF and HIF-1α, reducing angiogenesis in CRC.[43] [50] [51]
Epigenetic alterations, such as DNA methylation, histone acetylation, and microRNA regulation, can modify the expression of inflammatory mediators and directly influence NF-κB, PI3K/Akt, and Wnt/β-catenin pathway components. These changes reshape the inflammatory tone, alter cell-survival signaling, and enhance or suppress downstream oncogenic outputs.[52]
Regulation of MicroRNAs (miRNAs)
MicroRNAs (miRNAs) are master regulators of the genome, and their dysregulation is a hallmark of CRC. OncomiRs like miR-21 are frequently overexpressed in CRC, where they target and suppress tumor suppressor genes such as PTEN and PDCD4. miR-143 is a critical suppressor of the KRAS oncogene. Natural products that upregulate miR-143, such as certain marine-derived bioactives, inhibit the translation of KRAS, which shuts down the downstream MAPK/ERK signaling responsible for rapid cell proliferation.[53] [54]
Inhibition of Inflammatory Pathways Related to Gut Microbiota
Gut microbiota and their metabolites (e.g., SCFAs, bile acids, indoles) modulate epithelial immunity and frequently converge on NF-κB, either dampening or amplifying inflammatory responses. Microbial products can also affect MAPK and Akt activity, thereby influencing apoptosis, proliferation, and therapeutic sensitivity.[55] Together, epigenetic remodeling and microbiota modulation highlight the multidimensional impact of natural compounds on colorectal tumor biology ([Fig. 2]).
Classification of Natural Compounds with Anti-CRC Potential
Polyphenols
Most of the plant-derived bioactive compounds used as adjuvant therapy in the treatment of CRC contain polyphenols because of their therapeutic effects from different subtypes, which exhibit various biological activities contributing to their anticarcinogenic effects. Flavonoids, terpenes, terpenoids, central, and steroids are among the polyphenols studied for their roles in modulating pathways crucial to cancer development and progression[33] ([Table 1]).
Abbreviations: ↑, increases; ↓, decreases; Akt, protein kinase B; ATP, adenosine triphosphate; COX-2, cyclooxygenase-2; CRC, colorectal cancer; CSC, cancer stem cell; DNA, deoxyribonucleic acid; EPA/DHA, eicosapentaenoic acid/docosahexaenoic acid galectin-3, a protein that binds to specific sugars and plays a role in inflammation and cancer; L. helveticus, Lactobacillus helveticus; ER, endoplasmic reticulum; FAK, focal adhesion kinase; Fas, Fas cell surface death receptor; IGF-1, insulin-like growth factor 1; IL-6/STAT3, interleukin-6 and signal transducer and activator of transcription 3; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; miR, microRNA; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PDGF, platelet-derived growth factor; PI3K, phosphoinositide 3-kinase; PTN, pleiotrophin; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; SIRT1, silent information regulator 2 homolog 11; Smads, small mothers against decapentaplegic proteins; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor; Wnt/β-catenin, Wnt signaling pathway and β-catenin.
Curcumin
Source
It is a lipophilic polyphenol extracted from the rhizome of Curcuma longa (turmeric). Numerous in vitro studies support its therapeutic potential in CRC, demonstrating its impact on various molecular targets.[56]
Core Mechanism
Curcumin exhibits anti-CRC effects by targeting multiple oncogenic and inflammatory pathways. It acts by inhibition of NF-κB, JAK/STAT3, RAS/MAPK, and p53 signaling, leading to cell cycle arrest and apoptosis.[57] In vitro studies have shown that curcumin induces apoptosis and autophagy through the activation of caspase-3 and the suppression of p62 in CRC cell lines, such as HT29 and SW620 cells.
Evidence Tier
In in vivo models, curcumin reduced colitis-associated CRC by suppressing β-catenin, modulating p53, and attenuating inflammatory cytokines.[58] It also restored gut microbiota balance and improved metabolic profiles in AOM/DSS-induced CRC mice.[59] Clinically, curcumin and nano-curcumin formulations have shown potential as adjuvants, especially when combined with chemotherapy.[60] Regarding the safety of curcumin, it is considered safe; however, it has mild anticoagulant properties and may increase the effect of blood thinners such as warfarin or aspirin, increasing the risk of bleeding, particularly in patients undergoing surgery or chemotherapy.[61]
Safety and Pharmacokinetics
The pharmacokinetics of curcumin's clinical use are limited by its low solubility and bioavailability. Despite oral doses of 8 g/day in clinical studies, only small amounts of free curcumin were detected in plasma (2.5 ng/mL) due to rapid metabolism. Recent efforts have focused on improving its bioavailability through formulation strategies, such as curcumin analogs and nanoparticle encapsulation.[62] To enhance bioavailability, curcumin is often formulated in combination with piperine (from black pepper), which inhibits its metabolism. Liposomal formulations, nanoparticles, and phospholipid complexes have been used to increase its solubility and stability, improving curcumin's pharmacokinetics.[63]
Drug Interactions
It may also interact with drugs metabolized by the CYP3A4 and CYP2D6 enzymes, affecting their metabolism. Discontinue use at least 1 to 2 weeks before surgery or if taking anticoagulants. Monitor patients on chemotherapy for potential drug interactions[61] ([Table 2]).
Table outlining the mechanisms of action, effects on CRC, and study types of various bioactive compounds. It highlights their molecular targets and their roles in apoptosis, proliferation, and metastasis. The table also includes the natural sources of these compounds and their potential therapeutic effects in CRC treatment, based on in vitro, in vivo, and clinical studies
Note: Many natural compounds require high doses in clinical or preclinical studies due to poor bioavailability. This is often caused by low absorption, rapid metabolism, and first-pass effects. To improve bioavailability, advanced formulations like nanoparticles, liposomes, and phospholipid complexes are used. Strategies such as nanoparticle encapsulation, co-administration with enhancers like piperine, and lipid-based delivery systems help overcome these challenges.
Resveratrol
Source
It is a polyphenolic compound particularly abundant in sources like grapes, peanuts, and red wine.
Core Mechanism
Many studies showed that resveratrol activates silent information regulator 2 homolog 1 (SIRT1), influencing several cellular signaling pathways.[64] It suppresses cell proliferation, enhances apoptosis, and downregulates COX-2 and NF-κB, while influencing PI3K/Akt, Wnt/β-catenin, Notch, and SUMO1 pathways, which play a role in reducing the risk of inflammation and cancer.[65] [66]
Evidence Tier
In vitro, in CRC cell lines such as CaCo-2 and HCT-116, resveratrol inhibits PI3K signaling, promotes Fas redistribution, suppresses tumor cell survival, and induces apoptosis. It also shows anti-inflammatory and antioxidant effects.[67] An in vivo study indicated that resveratrol has anti-tumor activity by different mechanisms, such as Wnt/β-catenin, promoting apoptosis, anti-inflammatory, and antioxidant roles. Often this property is enhanced when combined with 5-fluorouracil, irinotecan, or quercetin; notably, zein nanoparticle formulations enhance its cytotoxic, pro-apoptotic, and oxidative effects, offering improved bioavailability and therapeutic potential.[68] [69] In humans, the only randomized controlled trial (RCT), a phase I study of micronized resveratrol (SRT501), demonstrated good tolerability and increased tumor apoptosis in patients with hepatic metastases from CRC, but clinical outcomes remain unproven.[70] Preclinical evidence consistently supports anti-tumor, anti-inflammatory, and antioxidant roles, often enhanced when combined with 5-fluorouracil, irinotecan, quercetin, or exercise.[68] [69]
Safety and Pharmacokinetics
Resveratrol is generally well-tolerated at low to moderate doses, but high doses may potentiate the effects of anticoagulant drugs, increasing the bleeding risk. Regarding the pharmacokinetics, trans-resveratrol has low oral bioavailability due to rapid metabolism and extrusion by ABC transporters like P-glycoprotein, MRP2, and BCRP in the intestine. Despite this, it shows health benefits, and co-administration with piperine can enhance its bioavailability by inhibiting metabolism.[71] Nanoparticle formulations, liposomes, and resveratrol-loaded nanoparticles (e.g., poly(lactic-co-glycolic acid) [PLGA] nanoparticles) are used to enhance its bioavailability and tissue targeting.[72]
Drug Interactions
Resveratrol modulates CYP3A4 and CYP2D6, which could interfere with the metabolism of chemotherapy agents such as paclitaxel and cyclophosphamide. Use with caution in patients on blood thinners or chemotherapy. Monitor for signs of bleeding and adjust doses of chemotherapy drugs accordingly[73] ([Table 2]).
Epigallocatechin-3-gallate (EGCG)
Sources
Green tea is considered one of the most common sources of EGCG, which is a bioactive polyphenol with potent cancer prevention properties, particularly in CRC ([Table 1]).
Core Mechanism
EGCG exhibits multiple anticancer mechanisms by targeting gene expression of colorectal cancer stem cells (CSC), reducing cancer cell proliferation via Wnt/β-catenin suppression,[74] enhancing apoptosis, modulating gut microbiota, anti-inflammatory pathways, Wnt signaling, DNA methylation, and β-catenin suppression,[75] [76] [77] inducing endoplasmic reticulum stress, and reducing colon-cancer-initiating cells.[78]
Evidence Tier
In vitro studies reduce proliferation and enhance apoptosis in CRC models, particularly by suppressing Wnt/β-catenin signaling and targeting CSCs.[74] Preclinical studies show that EGCG reduces tumor formation and precancerous lesions, with evidence of modulation of the gut microbiota and inflammatory pathways.[78] Several large RCTs have assessed EGCG/GTE in colorectal adenoma prevention. In a US-based phase II trial, Polyphenon E was well tolerated but did not significantly reduce rectal aberrant crypt foci.[79] The MIRACLE trial showed a trend toward preventive effects in patients post-polypectomy, though the results were not statistically significant.[80] Although EGCG shows promise in preventing CRC progression, clinical evidence is inconclusive, with no significant reduction in rectal aberrant crypt foci or large polyp recurrence in human trials.[78] [79] [80]
Safety and Pharmacokinetics
EGCG is generally well-tolerated at moderate doses, but high doses may interfere with drug metabolism. Regarding the pharmacokinetics, EGCG shows a lower bioavailability of approximately 26.5% after oral administration in mice, with higher tissue concentrations in the small intestine and colon. However, co-administration with piperine or curcumin increased EGCG plasma levels. These findings highlight species differences and suggest that dietary components can enhance EGCG bioavailability.[81] Nano-formulations (e.g., EGCG-loaded nanoparticles), liposomal encapsulations, and inclusion in phospholipid complexes are used to enhance its stability, solubility, and bioavailability.[82] Regarding the dose, EGCG was given to male CF-1 mice at 10 mg/kg (i.v.) or 75 mg/kg (i.g.).[81] Nanotechnology is being explored to improve EGCG's bioavailability and stability. pH-sensitive and ligand-targeted nanoparticles enhance gastrointestinal stability and selective delivery, increasing cytotoxicity and pro-apoptotic effects in preclinical CRC models.[83]
Drug Interactions
EGCG can inhibit CYP enzymes, particularly CYP1A2, which may affect the metabolism of drugs such as caffeine and theophylline. It may also interact with certain chemotherapy drugs, reducing their effectiveness by neutralizing oxidative stress. Avoid high-dose EGCG during chemotherapy or radiotherapy. Limit intake in individuals with caffeine sensitivity or those taking medications metabolized by CYP1A2[84] ([Table 2]).
Ellagic Acid (EA)
Source
Grapes and pomegranates are a good source of ellagic acid (EA). It serves as a potent multifunctional substance with protective effects against oxidative stress.
Core Mechanism
EA suppresses tumor growth and proliferation by modulating the PI3K/Akt and Wnt/β-catenin signaling pathways,[85] attenuates inflammation through downregulation of NF-κB, COX-2, inducible nitric oxide synthase (iNOS), TNF-α, and IL-6,[86] and enhances apoptosis via p53 upregulation and AMPK/mTOR and Bax/Bcl-2 pathways.[87] [88] EA also targets CSC and activates endoplasmic reticulum stress signaling.[78]
Evidence Tier
In vitro study shows, EA and ellagitannin-rich compounds exert strong anticancer effects by suppressing tumor growth and proliferation in CRC models. These compounds also reduce oxidative stress and inflammation.[89] In vivo studies show, EA suppresses tumor growth and regulates multiple signaling pathways involved in CRC progression. EA has shown potential as a multi-target chemopreventive agent.[85] Human clinical evidence, however, remains limited. A clinical RCT supplemented 35 CRC patients with 900 mg/day of ellagitannin-rich pomegranate extract before surgery. Gene expression was modulated in both normal and cancerous colon tissues, but the effects were modest, variable across individuals, and not linked to clinical outcomes such as tumor regression or survival.[90] Despite promising preclinical data, clinical evidence remains limited and inconclusive regarding the effectiveness of EA in human CRC treatment.
Safety and Pharmacokinetics
Regarding safety, at high doses, EA may cause gastrointestinal issues such as nausea or diarrhea. It can also interfere with the absorption of iron, potentially leading to anemia. Caution is advised for individuals with a history of kidney stones.[91] [92] There are no major concerns regarding drug interactions, but caution is advised for individuals with gastrointestinal or iron absorption issues. Regarding the pharmacokinetics, free EA has an extremely low oral bioavailability in humans, typically estimated at less than 1%. Following a standard 80 mg oral dose in humans, the peak plasma concentration of free EA is approximately 320.7 ng/mL.[93] Various nano formulations, including chitosan, zein, gold, and zinc oxide carriers, have enhanced EA's stability, colonic retention, and oral absorption, leading to stronger antioxidant, anti-inflammatory, and anticancer effects in vitro and in vivo.[83] [94] EA nanoparticles demonstrated improved cellular uptake, ROS scavenging, and sustained release, thereby amplifying biological efficacy and therapeutic potential, particularly in colorectal and inflammatory bowel disease models[92] ([Table 2]).
Drug Interactions
According the previous studies on the compound, no significant drug–drug interactions were recorded.
Flavonoids
Flavonoids, as a specific type of polyphenol, are important for both the prevention and treatment of CRC. They are present in fruits, vegetables, tea, and wine as chemopreventive agents. By functioning as potent antioxidants, flavonoids decrease oxidative stress, one of the main aspects of carcinogenesis, and affect cell proliferation, apoptosis, angiogenesis, and metastasis.[33] One of the defining features of flavonoids is their structural diversity, which translates into an array of biological functions. The major categories include flavones, flavanols, flavanones, isoflavones, and anthocyanidins, each exhibiting unique biochemical activities[95] ([Table 1]).
Quercetin
Source
Quercetin is a flavanol widely distributed in plants. Major dietary sources include onions, apples, berries, grapes, broccoli, green tea, and buckwheat.[96]
Core Mechanism
Quercetin has demonstrated the capability to suppress cancer cell proliferation in CRC through the modification of signaling pathways.[97] Also, according to the findings of Fu et al, quercetin suppresses VEGF-A linked with NF-κB modulating p38 MAPK, inducing AMPK, and influencing multiple molecular targets (e.g., AKT1 and MMP9 in cancer cells). p65 expression in HT-29, also in HUVECs, inhibits the expression and translocation of VEGFR-2, which leads to inhibition of CRC.[98]
Evidence Tier
Numerous cell-based studies show quercetin inhibits pro-inflammatory cytokines, reduces oxidative stress, and suppresses malignant cell proliferation, all of which contribute to its anticancer properties.[99] In vivo animal models demonstrate cardiovascular, neuroprotective, anti-diabetic, and anticancer effects in rodents.[100] Several human intervention studies have been conducted (e.g., supplementation trials for inflammatory markers and metabolic parameters), but they are limited in size and consistency.[96] Some randomized controlled trials report reductions in C-reactive protein and improvements in certain cardiovascular or metabolic endpoints at doses >500 mg/day.[96] However, no large definitive human outcome trials currently support quercetin as a therapeutic agent.
Safety and Pharmacokinetics
Quercetin is generally safe, but in high doses quercetin may lead to headaches, tingling sensations in the arms, and kidney issues. It is absorbed poorly in the intestines, undergoes extensive first-pass metabolism in the liver, and is primarily excreted as metabolites (quercetin glucuronides and sulfates) via urine. It has low bioavailability (2–10%) due to its poor absorption and rapid metabolism. Peak plasma levels are reached 1 to 2 hours after ingestion.[101] Quercetin can interact with blood thinners, increasing bleeding risks. It is important to monitor its intake, especially for those on medication.[102] Quercetin is often formulated in nano-liposomes and phospholipid complexes to improve its low bioavailability, with doses of 50 to 100 mg/kg showing anticancer effects in animal studies. These formulations enhance solubility, cellular uptake, and therapeutic efficacy, particularly in CRC[103] ([Table 2]).
Drug Interactions
According to previous studies on the compound, no significant drug–drug interactions were recorded.
Naringenin
Source
It is a flavanone found in citrus fruits (e.g., grapefruit, oranges) and is also produced by hydrolysis of its glycoside form, naringin.[104]
Core Mechanism
The anticarcinogenic activity of naringenin may occur through various mechanisms, including enhancement of apoptosis, metabolic suppression, enhancement of carcinogen detoxification, antioxidant action, and oncogene inactivation.[105] Naringin reduced CRC formation by inhibiting the NF-κB/interleukin-6 and signal transducer and activator of transcription 3 (IL-6/STAT3) pathway.[106] Also, it inhibits signaling pathways, including PI3K/Akt/mTOR and Wnt/β-catenin in CRC cell lines.[104] In addition, it induces downregulation of MMP-2/MMP-9, regulating miRNAs (e.g., miR-216a targeting CEMIP/KIAA1199) and inhibiting EMT processes in CRC cell lines (HCT116, LOVO) with the flavanone naringin (precursor of naringenin)[106] ([Table 1]).
Evidence Tier
Several in vitro studies show that naringenin and its precursor reduce cell proliferation, induce apoptosis, and inhibit migration in CRC cell lines (e.g., HCT116).[107] In animal models, naringin (precursor of naringenin) reduced colitis and colorectal adenoma formation in a murine model (C57BL/6).[104] Clinical data on naringenin's effects in humans are still limited, but emerging studies suggest potential benefits in CRC prevention and treatment.[108]
Safety and Pharmacokinetics
Naringenin has low oral bioavailability partly due to poor absorption and extensive metabolism (mainly glucuronidation and sulfation) after ingestion, with bioavailability estimates of approximately 15%.[104] Liposomal delivery systems and nanoemulsions are the leading technologies used to overcome the inherent poor water solubility and rapid first-pass metabolism of naringenin[109] ([Table 2]).
Drug Interactions
It can interact with CYP3A4 inhibitors or inducers, affecting drug metabolism, and may increase the effects of certain medications, including statins. It could interfere with antihypertensive medications.[110]
Luteolin
Source
Numerous fruits and vegetables, such as carrots, peppers, celery, broccoli, and onions, naturally contain the flavonoid luteolin.
Core Mechanism
Luteolin has been shown to fight cancer in many cancer types, including CRC, via mitochondrial/caspase pathways (decrease Bax, increase Bcl-2, cytochrome c release),[111] modulation of key signaling axes such as IL-6/STAT3,[112] and impact on oxidative stress, pyroptosis, Wnt/β-catenin, MAPK, and other pathways according to recent reviews.[113] MicroRNA-384 (miR-384) is a strong tumor suppressor. Luteolin can make CRC cells and tissues express more miR-384 and less pleiotrophin (PTN).[114] Also, lutein can prevent the production of the mesenchymal form in the epithelial form in CRC cells.[115]
Evidence Tier
Many in vitro CRC cell-line studies (e.g., HT-29, SW480, SW620) demonstrate reduction of viability, induction of apoptosis, and reduced migration/invasion.[111] Some animal (in vivo) studies of colon carcinogenesis or CRC xenograft models show that luteolin reduces tumor growth or metastasis, for instance, the study on HT-29 xenograft in mice in combination therapy.[116] Recently, luteolin's antitumor properties have been investigated by numerous researchers, especially in treating CRCs, and identified the beneficial effects in the treatment of CRC, through apoptosis and promoting cell cycle arrest.[117] There are limited clinical data on luteolin in CRC, but preclinical evidence supports its potential as an effective therapeutic agent.[118]
Safety and Pharmacokinetics
Luteolin has estrogenic effects, so it should be avoided by pregnant women.[119] Luteolin has low bioavailability (approximately 4% in rats at 50 mg/kg), but its absorption can be improved with optimized delivery systems such as polymeric micelles, phospholipid complexes, and ROS-responsive nanoparticles. At doses of 50 and 200 mg/kg, bioavailability increases to approximately 4.1 and 17.5%, respectively.[120] [121] [122] [123] To improve bioavailability, luteolin is encapsulated in liposomes, nanoparticles, or administered in combination with surfactants to enhance its solubility and stability[120] [124] ([Table 2]).
Drug Interactions
Some in vitro and in vivo data show that luteolin can inhibit cytochrome P450 enzymes and organic anion transporting polypeptides (OATPs), suggesting potential for altered pharmacokinetics of co-administered drugs, especially with drugs metabolized by the liver. Monitoring for interactions is prudent.[119] [121]
Genistein (Soybean)
Source
Genistein is an isoflavonoid found abundantly in soybeans, which is a rich source of natural bioactive compound pathways.[125] Soybeans include two kinds of isoflavones: daidzin (DAI) and genistin (GEN). Several investigations have demonstrated that GEN has anticancer effects.[126]
Core Mechanism
Genistein has been shown to inhibit CRC cell proliferation, induce apoptosis, and trigger cell cycle arrest (e.g., via ATM/p53-dependent G2/M arrest in human colon cancer cells).[127] It modulates multiple signaling pathways, including the Wnt/β-catenin, PI3K/Akt, NF-κB, MAPK/ERK, and JAK/STAT pathway.[128] It reduces invasion/migration of CRC cells via epigenetic upregulation of tumor suppressors (e.g., WIF1), downregulation of MMP2/MMP9, and reduction of FLT4 expression, thereby affecting metastasis.[129] Numerous in vitro studies show genistein reduces the viability and migration of CRC cell lines (e.g., HT-29, HCT116)[130] ([Table 1]).
Evidence Tier
In vivo models of CRC (e.g., HCT-116 cells in nude mice) treated with genistein showed tumor growth suppression in a dose-dependent fashion.[131] There is limited human trial evidence specific to CRC. One registered study (NCT01985763) investigates genistein added to FOLFOX/FOLFOX-Avastin in stage IV colorectal/rectal cancer patients.[132] Thus, translation to human CRC therapy remains preliminary.
Safety and Pharmacokinetics
Genistein is generally safe at doses up to 1,000 mg/day, though higher doses may cause gastrointestinal discomfort. It has low bioavailability (5–15%) due to poor absorption and first-pass metabolism in the liver.[133] After ingestion, genistein is metabolized into glucuronide and sulfate conjugates, which circulate in the plasma. Plasma concentrations peak within 1 to 2 hours, with a half-life of 9 to 15 hours. Genistein is mainly excreted in the urine as metabolites. Despite its low bioavailability, its effects are mediated through these metabolites, influencing pathways involved in cancer cell growth and inflammation.[133] [134] Nano-formulations, liposomes, and phospholipid complexes have been employed to enhance its absorption, stability, and tissue targeting.[135]
Drug Interactions
Genistein interacts with cytochrome P450 enzymes: for example, isoflavones can inhibit phenol-sulfotransferases and may affect the metabolism of drugs such as warfarin, diclofenac, phenytoin, tolbutamide, and losartan.[136] High doses of genistein may interfere with thyroid function and may act as a phytoestrogen, affecting hormone-sensitive conditions like breast cancer. Genistein should be used cautiously in those undergoing hormone replacement therapy (HRT) or with hormone-sensitive conditions[137] ([Table 2]).
Terpenes and Terpenoids
Terpenes and terpenoids, natural chemicals originating from microorganisms and plants, have sparked significant attention in oncology because of their diverse effects in suppressing cancer progression.[138]
Terpenes are hydrocarbons made of isoprene units, while terpenoids are their oxygenated forms with diverse functional groups. These compounds can target various aspects of tumor biology, such as NF-κB, PI3K/Akt/mTOR, and Wnt/β-catenin,[138] [139] alter the tumor microenvironment, and enhance immune responses (e.g., increased antigen presentation) in CRC models.[140] Moreover, limonene and perkily alcohol, citrus-derived terpenoids, inhibit CRC by suppressing Ras signaling and downregulating COX-2, a key inflammatory mediator. They also enhance the effects of chemotherapy while reducing its systemic toxicity.[141] Many CRC cell line (in vitro) studies show terpenoids reduce viability, induce apoptosis, inhibit migration/invasion, alter cell signaling, inhibit angiogenesis, oxidative stress, and mitochondrial dysfunction, making them promising candidates for cancer therapy.[139] [142] Some in vivo studies of animal xenograft or carcinogenesis models of CRC report tumor volume reduction or metastasis inhibition as a result of using various terpenes and terpenoids (e.g., safranal, menthol, and linalool have been used in cell/animal model).[142] [143] Regarding the safety and pharmacokinetics,
Most terpenes are rapidly absorbed through the gastrointestinal tract. Bioavailability is typically low for many terpenes and terpenoids due to poor water solubility and rapid metabolism. However, their bioavailability can be enhanced with the use of specific formulations, such as liposomal delivery systems or by combining them with other compounds like piperine (from black pepper) that can enhance absorption.[144] [145] [146] Plasma concentrations are achieved within 1 to 2 hours, but they tend to decline rapidly due to their short half-lives (usually within a few hours). They are primarily metabolized by the liver through cytochrome P450 enzymes, and their metabolic fate can lead to various bioactive metabolites.
Terpenes and terpenoids can interact with drugs by inhibiting cytochrome P450 enzymes, affecting the metabolism of drugs like statins and benzodiazepines. They may also enhance the effects of anticoagulants (e.g., warfarin), increase sedation when combined with CNS depressants, and alter the absorption of medications like cyclosporine. Caution is needed when using terpene-based supplements with other medications[147] [148] ([Table 1]).
Oridonin
Source
Oridonin is the major metabolic derivative of Rabdosia rubescens, a plant known for its anticancer properties.[149]
Core Mechanism
Oridonin exerts its antitumor action in some tumors, mainly via modulating multiple signaling pathways: for example, it upregulates BMP7 and activates p38 MAPK in HCT116 cells.[150] The alteration of transforming growth factor-β1 (TGF-β)/small mothers against decapentaplegic proteins (Smads) signaling pathway dose-dependently suppresses CRC proliferation. TGF-β regulates normal colon physiology and contributes to CRC formation, angiogenesis, progression, immune evasion, and metastasis,[151] [152] [153] and reduces PKM2 dimer formation and prevents nuclear translocation in CRC.[154] In vitro studies of multiple cell lines (e.g., HCT116, SW620, SW1116) demonstrate dose-dependent inhibition of proliferation, apoptosis induction, and cell cycle arrest.[149]
Evidence Tier
In vivo studies of xenograft models in mice (e.g., SW1116 in nude mice) showed significant tumor growth inhibition with oridonin treatment.[149] Limited clinical data are available for human trials, but preclinical studies indicate promising therapeutic potential in CRC.
Safety and Pharmacokinetics
Oridonin can cause gastrointestinal distress, including nausea and vomiting. There is also limited safety data on the long-term use of oridonin, so it should be taken with caution, especially for individuals with pre-existing health conditions.[155] The oral bioavailability of oridonin in rats is very low (about 4–11%) and is rapidly absorbed with a short time to peak plasma level after oral administration in animal studies. It follows first-order pharmacokinetics and shows low systemic exposure due to first-pass effects.[156] Liposomal formulations and nanoparticles are explored to improve its pharmacokinetics and bioavailability.[157]
Drug Interactions
Research in animals shows that inhibitors like verapamil can increase the plasma concentration and systemic exposure of oridonin by inhibiting efflux transport and metabolism, suggesting P-gp and CYP involvement in its pharmacokinetics.[158] Oridonin has been formulated in nano-delivery systems (e.g., nanocrystals, liposomes, nanoparticles) to improve its solubility and delivery[159] ([Table 2]).
Citral
Source
A bioactive component derived from essential oils of lemongrass and citrus fruits, citral is particularly significant in cancer research for its potential role in preventing CRC. This acyclic monoterpene aldehyde, known for its lemony scent, comprises two main isomers: geranial and neural. Its therapeutic effects are linked to the alteration of key cellular processes that are involved in cancer progression.[160]
Core Mechanism
Citral increases the expression of Bax and P53 decreases Bcl-2, leading to cancer cell death,[161] reducing the activity of NF-κB and COX-2, thus lowering cytokines like IL-6 and TNF-α[162] ([Table 1]).
Evidence Tier
The most advanced evidence on citral's effects in CRC comes from in vitro and in vivo studies. Several studies have been conducted on CRC cell lines, such as HCT116 and SW480, which showed that citral significantly reduces cell viability and tumor growth. Additionally, animal models have demonstrated that citral inhibits tumor progression and metastasis.[163]
Safety and Pharmacokinetics
Citral's bioavailability is generally considered low and unstable in its free form, but researchers are developing advanced delivery systems like nanoparticles and phytosomes to overcome this by improving stability, absorption, and efficacy for better drug delivery.[164] Nanocarriers, liposomes, and inclusion in phospholipid complexes are utilized to improve stability and bioavailability of cital.[165] Citral can cause skin irritation or allergic reactions in some individuals. Ingesting high doses of citral may lead to gastrointestinal issues such as heartburn or nausea. Citral can also interact with sedatives or alcohol, potentiating central nervous system depression.[166]
Drug Interactions
Citral has been shown to interact with certain sedatives, increasing the risk of central nervous system depression. It may also interact with drugs metabolized by the cytochrome P450 enzyme system. Therefore, caution is advised when co-administering citral with these medications, especially in high doses[167] ([Table 2]).
Zerumbone
Source
Zerumbone, a sesquiterpene ketone found in Zingiber zerumbet Smith, has also shown promise in CRC treatment. Studies indicate that zerumbone inhibits tumor growth associated with Enterotoxigenic Bacteroides fragilis (ETBF) infection by reducing colonic inflammation without affecting ETBF colonization.[168]
Core Mechanism
Zerumbone has been shown in multiple in vitro CRC cell lines (e.g., HCT116 SW48) for decreased viability, invasion, and EMT markers.[169] It promotes apoptosis in CRC cell lines such as HCT116, SW620, and HT29 through upregulation of death receptors DR4 and DR5, facilitating TRAIL-mediated apoptosis. Additionally, it induces mitotic arrest and inhibits the survival of HCT116 and SW48 cells.[168] [169] The biological activity of zerumbone is primarily attributed to its α,β-unsaturated carbonyl group, which depletes intracellular glutathione (GSH) and increases redox potential (E).[169] Also, zerumbone modulates the focal adhesion kinase (FAK)/PI3K/NF-κB/uPA signaling axis.[169] Broad reviews indicate zerumbone acts via pathways such as NF-κB, Akt, and IL-6/JAK2/STAT3, which are relevant across cancers, including CRC.[170] It downregulates β-catenin, a crucial factor in CRC development, and modulates STAT3 and β-catenin signaling pathways. Zerumbone's anti-inflammatory actions are central to its anti-CRC effect, particularly in models involving ETBF infection.[171] Moreover, zerumbone inhibits TNF-α in HCT116 cells.[172] It inhibits FAK, a tyrosine kinase involved in cell–extracellular matrix interactions[169] ([Table 1]).
Evidence Tier
In in vitro CRC studies, zerumbone has been used at concentrations of approximately 5 to 20 µM (for example, in the HCT116 colon cancer cell line) to induce anti-proliferative effects.[172] The evidence is preliminary and preclinical; e.g., one study showed that a combination of zerumbone with the standard chemotherapy agent 5-fluorouracil enhanced tumor growth inhibition in a CRC model.[173] Oral doses in animal models (not exclusively CRC) include, e.g., approximately 100 to 500 ppm in the diet in mice, which significantly inhibited colon adenocarcinoma multiplicity.[170]
Safety and Pharmacokinetics
Zerumbone is generally considered safe at low to moderate doses, with studies showing no significant toxicity in animal models. It has a low incidence of adverse effects, but higher doses may cause gastrointestinal disturbances such as nausea, vomiting, or diarrhea.[174] Zerumbone is highly lipophilic and poorly soluble in aqueous media (approximately 1.3 mg/L in water), which leads to low oral absorption and bioavailability; accordingly, formulation strategies such as liposomal and nanoparticle formulations, nano-encapsulation, inclusion complexes, or lipid-based carriers are required to improve its delivery[175] ([Table 2]).
Drug Interactions
Zerumbone has shown potential for drug–drug interactions primarily in a research context, enhancing the effects of certain chemotherapy drugs and radiation therapy, and showing antagonistic effects with some other compounds.[176]
Steroids
Steroids derived from natural products, such as withanolides, diosgenin, and certain steroidal alkaloids and saponins, are being investigated for their potential anticancer properties in the treatment of CRC. These compounds, often referred to as nutraceuticals, modulate various molecular targets and signaling pathways to inhibit cancer growth, often with fewer side effects than conventional treatments in preclinical studies[177] ([Table 1]).
Ergosterol Peroxide (EP)
Source
In traditional medicine, mushrooms are considered valuable therapeutic agents in the treatment of various diseases. In Russia and Western Siberia, the Chaga mushroom (Inonotus obliquus) is used as a natural compound for the treatment of some diseases of gastric and different cancer types.[178]
Core Mechanism
Recent studies have highlighted that ergosterol peroxide (EP) is used in suppressing cancer and inflammation.[179] Also, it suppresses LPS-induced expression of pro-inflammatory genes in RAW264.7 macrophage-like cells and inhibits the proliferation of HT-29 colon adenocarcinoma cells.[179] Further investigations have demonstrated that EP induces apoptosis in CRC cells, as evidenced by flow cytometry (FACS) analysis and Western blotting. It also reduces HCT116, HT-29, SW620, and DLD-1, each exhibiting varying sensitivity.[90] EP generates ROS in cancer cells, although this effect is partially attenuated by STAT1 signaling inhibition.[180] EP also suppressed inflammatory signaling (NF-κB, MAPKs) and oxidative stress in HT29 cells and upregulated CDKN1A (p21) while suppressing STAT1 in colon adenocarcinoma cells.[180]
Evidence Tier
In vitro CRC cell-line studies used EP to show growth inhibition via mechanisms such as β-catenin downregulation.[181] In a preclinical study (in vivo study) of an azoxymethane/dextran-sodium-sulfate (AOM/DSS) mouse model of colon carcinogenesis, EP given orally reduced tumor formation, though the exact mg/kg dose was not standardized in the published report.[179]
Safety and Pharmacokinetics
EP is highly tolerable in preclinical models, with mice showing no signs of toxicity or organ damage at doses up to 500 mg/kg. It is metabolically stable in liver microsomes and plasma, yet its oral bioavailability remains low due to poor aqueous solubility and high lipophilicity. Although human data are limited, related models indicate a maximum plasma concentration (Cmax) of approximately 2.27 µg/mL reached 8 hours post-administration. To overcome these pharmacological barriers, recent research emphasizes using nanostructured lipid carriers (NLCs) and synthetic derivatives to enhance absorption and clinical efficacy[182] [183] ([Table 2]).
Drug Interactions
EP can be metabolized by gut bacteria with conversion to more potent metabolites against CRC cell lines (e.g., M2, M3 in Caco-2, DLD-1), suggesting involvement of gut metabolism.[184] EP displays a favorable safety profile with minimal potential for conventional drug–drug interactions (DDIs).[183]
Fatty Acids and Lipids
Source
Marine microalgae are known to be an excellent source of polyunsaturated fatty acids (PUFAs), with levels often exceeding 80%, particularly rich in both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Core Mechanism
Both EPA and DHA have been found to block key angiogenic factors like platelet-derived growth factor, VEGF, and endothelial cell growth factor, making them more effective against breast cancer, CRC, and existing adenocarcinomas. Studies have shown that EPA and DHA, whether they are in their acid form or phospholipids, can inhibit CRC cells' growth. PUFAs have been shown to have a potential suppressive effect on growing HT-29 CRC cell line compared with Caco-2 and DLD-1 cell lines.[185]
Evidence Tier
Many in vitro CRC cell-line studies show that manipulating fatty-acid metabolism or supplying certain fatty acids affects CRC cell proliferation, apoptosis, and migration. For example, butyrate treatment of CRC cells shows histone deacetylase (HDAC) inhibition.[186] Specific fatty acids (e.g., short-chain fatty acids such as butyrate) exert anti-tumor effects by inhibiting HDACs, promoting differentiation and apoptosis in colon epithelial/CRC cells.[186] Omega-3 PUFAs (e.g., EPA, DHA) may modulate inflammation, reduce pro-tumor eicosanoids (from omega-6 pathways), influence immune responses, reduce cell-proliferation signaling, and sensitize tumor cells to therapy.[187] Animal models (especially colitis-associated CRC or xenograft CRC) indicate that diets enriched in omega-3 PUFAs reduce tumor incidence or progression.[188] Although regarding clinical signaling, no large-scale trials definitively establish fatty acids or lipids as standalone treatments in CRC, the accumulating data suggest adjunctive/preventive potential. For example, a review on PUFAs says they “might influence CRC” as adjunct therapies to currently existing treatment modalities.[187]
Safety and Pharmacokinetics
EPA and DHA are generally safe when consumed within recommended doses.
Bioavailability of EPA and DHA is enhanced when consumed with fat-containing meals or in advanced formulations. Pharmacokinetically, EPA typically reaches peak plasma concentrations faster but has a shorter half-life compared with DHA. Although generally well-tolerated, monitoring may be advisable for individuals on anticoagulants.[189] Clinical investigations of long-chain omega-3 PUFAs in CRC or adenoma prevention have used doses of approximately 1 to 2 g/day (e.g., EPA 2 g/day reduced adenoma number in a trial).[190] These PUFAs are usually administered as fish-oil capsules or triglyceride/ethyl ester preparations; no specialized delivery system for CRC targeting is standard yet.[191] Oral administration shows incorporation into colonic mucosa and plasma phospholipids, though absolute systemic and tissue bioavailability vary widely depending on formulation and background diet; e.g., oral omega-3 PUFAs increased ileal luminal concentrations in humans with ileostomy[192] ([Table 2]).
Drug Interactions
According to previous studies on the compound, no significant drug–drug interactions were recorded.
Polysaccharides
Source
Natural polysaccharides (complex carbohydrates derived from plants, fungi, algae, and medicinal mushrooms) have been investigated for anti-colorectal cancer activity.[193] Polysaccharides such as pectin, alginate, chitosan, and guar gum are frequently formulated into colon-targeted delivery systems (microspheres, nanoparticles, coatings) to carry anticancer drugs or bioactives to the colon.[194]
Core Mechanism
Numerous studies show polysaccharides derived from plants or fungi inhibit CRC cell-line proliferation (e.g., HCT116, HT-29), induce apoptosis, and downregulate cyclin D1/Bcl-2/VEGF/MMPs.[195] Apple polysaccharides (AP) have been shown to moderately inhibit tumorigenesis in colonic epithelial cells. One proposed mechanism involves the inhibition of galectin-3, a β-galactoside-binding lectin implicated in inflammation, tumor progression, and metastasis.[196] AP appears to block galectin-3 from binding to its ligands, thereby promoting apoptosis and potentially preventing tumor formation.[196] Fucoidan, a sulfated polysaccharide extracted from brown seaweeds, exhibits potent anti-CRC properties. Experimental studies have shown that fucoidan induces apoptosis in CRC cell lines such as HT-29 and HCT116.
Evidence Tier
In vivo study on animal models of colon/colorectal tumorigenesis shows suppressed tumor growth, improved immune markers, modulated gut microbiota, and reduced metastasis in some cases.[197] Furthermore, numerous studies, including clinical trials, provide the anti-CRC activity of fucoidan in humans, with lower adverse effects.[198] Some adjuvant clinical use (e.g., PSK) shows improved survival in certain cancers (including possibly CRC), but robust human clinical trials specifically in CRC treatment are limited.[197]
Safety and Pharmacokinetics
Because polysaccharides are large, poorly absorbed molecules and are often used for local delivery in the colon, systemic bioavailability is limited; the formulation goal is local release rather than high systemic levels.[194]
In recent studies, bioactive polysaccharides are widely recognized for their excellent safety profile, characterized by minimal toxicity. Despite their safety, natural polysaccharides often suffer from low oral bioavailability, frequently less than 10% due to their large molecular size and poor absorption across intestinal barriers. To overcome these limitations, advanced nano-delivery systems like liposomes and hydrogels are being utilized to enhance their absorption and target specificity. Pharmacokinetically, some polysaccharides reach peak plasma concentrations within a few hours but exhibit long half-lives, indicating sustained systemic presence. Furthermore, many polysaccharides provide health benefits through indirect pathways, such as being metabolized by gut microbiota into bioactive short-chain fatty acids.[199] [200]
Drug interactions
According to previous studies on the compound, no significant drug–drug interactions were recorded ([Table 2]).
Fermented Natural Products
Source
Bovine skim milk fermented by Lactobacillus helveticus has illustrated promising results, as the strains were able to grow well in acidic conditions in the milk. This growth leads to the production of a variable strength biological compound depending on the specific strain used, as well as factors like pH, temperature, fermentation time, and the high amount of bioactive compounds released during fermentation that can suppress oxidation and the risk of cancer cells progression. Overall, Lactobacillus helveticus strains show potential for producing bioactive substances with both properties of antioxidative and anticancer effects.[201]
Core Mechanism
The fermented extract showed selective inhibition of cancer cells and minimal effect on normal colon cells in vitro, which is a positive preliminary safety indicator. In the HT-29 human colon cancer cell line, extracts of fermented skim milk inhibited cell growth (up to approximately 50.98% growth inhibition for one strain at 12 h fermentation) while showing minimal effect on normal colon cells.[201]
Safety and Pharmacokinetics
Bovine skim milk fermented by Lactobacillus helveticus is recognized as a safe and highly bioavailable functional food. Its safety is established through its “generally recognized as safe” clinical trials showing no adverse effects on blood serum variables or physical health during long-term ingestion. These peptides show poor bioavailability when administered in water; the fermented milk matrix significantly enhances their absorption and biological efficacy in vivo. Plasma concentration studies indicate that regular consumption leads to measurable systemic changes, such as increased serum calcium and modulated cytokine levels, which correlate with improved bone density and immune function ([Table 2]).
Drug Interactions
No specific drug–drug interactions have been reported in current studies. Further clinical studies are required to assess any potential interactions with other therapies.[202] [203]
Gums and Natural Polymers
Source
Natural gums and oleo-gum resins, such as those derived from Mimusops ferrea (M. ferrea), as well as polysaccharide-based nanoparticles (e.g., guar gum mesoporous silica nanoparticles).[204]
Core Mechanism
Treatment with non-polar fraction (RH) led to mitochondrial outer membrane reduction potential in HCT116 cells, suggesting activation of mitochondrial-mediated apoptotic pathways. In addition, RH triggered nuclear apoptosis; these findings also point to the possible activation of necrotic cell death in HCT116 following RH exposure. A likely explanation for this dual apoptotic and necrotic effect is that RH promotes the generation of ROS, leading to DNA and mitochondrial membrane damage. Such mitochondrial damage impairs adenosine triphosphate (ATP) production, limiting caspase activation and ultimately pushing the cells toward necrosis after concisely activating the apoptotic pathway. Overall, these results suggest that RH possesses both antimetastatic and cytotoxic properties against human colon cancer cells.[204]
Evidence Tier
Several in vitro experimental setups show that polymer-based nanoparticles made with natural gums (e.g., guar gum mesoporous silica nanoparticles) loaded with anticancer drugs demonstrate cytotoxicity in colon cancer cell lines[205] and restore the balance in the microbial. In preclinical models, this mechanism has been shown to inhibit tumor formation and improve the efficacy of standard antitumoral therapy by positively influencing the tumor microenvironment.[206] Aberrant DNA methylation (silencing of tumor suppressor genes) and dysregulated histone deacetylases (HDACs) are key reversible hallmarks of human CRC pathology that drive uncontrolled cell growth.[207] Phytochemicals like curcumin and resveratrol function as natural DNMT and HDAC inhibitors. This action can reactivate silenced tumor suppressor genes and reverse pro-carcinogenic events, potentially overcoming drug resistance and improving response to chemotherapy[208] [209] ([Table 2]).
Safety and Pharmacokinetics
They are considered safe for therapeutic use, with toxicological studies establishing a high No-Observed-Adverse-Effect Level (NOAEL) of 500 mg/kg. Pharmacokinetic data indicate that active metabolites reach peak plasma concentrations rapidly, typically within 15 to 60 minutes after ingestion.[210] [211] No significant drug–drug interactions have been reported with RH or natural gum-based nanoparticles in current studies.
Drug Interactions
According to the previous studies on the compound, no significant drug–drug interactions were recorded.
When patients with CRC are undergoing active therapy (e.g., chemotherapy, immunotherapy), healthcare providers need to address the potential risks and benefits of using over-the-counter (OTC) supplements. OTC supplements, such as curcumin, resveratrol, or vitamin D, may interact with chemotherapy or immunotherapy drugs, potentially altering their effectiveness or increasing the risk of side effects. Counseling should focus on interaction management, including assessing the patient's full list of supplements and prescription medications to identify potential drug–supplement interactions, such as enhanced toxicity or reduced therapeutic efficacy.
Patients should be encouraged to openly interact about all supplements, including herbal remedies and nutraceuticals, taken with healthcare providers, which should be recorded in the patient's medical chart. Patients need to recognize that, especially if advised by their oncologists, some of these supplements may benefit from discontinuation (especially if there is risk for bleeding and modulation of cytochrome P450 enzymes, e.g., high-dose fish oil or polyphenols). The effects of supplements on the treatment plan and outcome need to be monitored and followed up regularly, so that safe, effective cancer treatments are not compromised. By encouraging honest communication, urging documentation of all supplement used, and cautious management of potential interactions, health care professionals can promote patient safety during active cancer treatment.
This review emphasizes the anticancer activities of natural compounds. We recognize the necessity to distinguish between nutraceutical dosing and dietary intake. High doses of these nutrients, used as drugs or supplements and not in nutritionally relevant doses, are referred to herein as nutraceutical dosing. The most widely studied agents have been those described above. For example, studies on curcumin have administered doses as high as 8 g/day, much higher than what is typically consumed in a regular diet. In contrast, dietary-pattern associations explore the correlation between habitual intake of foods rich in bioactive compounds, such as vegetables, fruits, or whole grains, and cancer risk reduction, which typically involves much lower compound concentrations. Although the review does discuss some interventional preclinical data and human observational studies, interventional human data from clinical trials are indeed limited, particularly with regard to the optimal dosing and bioavailability of these compounds in CRC. Therefore, further clinical studies are needed to evaluate both nutraceutical dosing and the clinical relevance of dietary intake patterns for CRC prevention and treatment.
Conclusion
CRC is one of the global health burdens with multifactorial pathogenesis and limited success from conventional therapies due to resistance, toxicity, and tumor heterogeneity. Natural products, derived from plants, marine organisms, and microorganisms, offer promising chemopreventive and therapeutic strategies. This review highlights a wide array of bioactive compounds, particularly polyphenols, flavonoids, terpenoids, and fatty acids, that exert anticancer effects through mechanisms including modulation of inflammation, oxidative stress, apoptosis, cell cycle arrest, epigenetic regulation, and gut microbiota composition. Notably, compounds such as curcumin, resveratrol, EGCG, and quercetin target critical molecular pathways like Wnt/β-catenin, PI3K/Akt, NF-κB, and MAPK, effectively suppressing the proliferation of cancer cells and elevating the efficacy of chemotherapeutic response.
Conflict of Interest
None declared.
Acknowledgments
The authors thank the College of Medicine for its continued institutional support.
Authors' Contributions
The authors confirm that the manuscript titled “Effect of Natural Products on the Prevention and Treatment of Colorectal Cancer” has been read and approved by all the authors. Each author meets the criteria for authorship as outlined on page 29 of the journal's guidelines, and each author believes that the manuscript represents honest and original work.
-
References
- 1 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
- 2 Ferlay J, Soerjomataram I, Dikshit R. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136 (05) E359-E386
- 3 Shivshankar S, Patil PS, Deodhar K, Budukh AM. Epidemiology of colorectal cancer: a review with special emphasis on India. Indian J Gastroenterol 2025; 44 (02) 142-153
- 4 Ionescu VA, Gheorghe G, Bacalbasa N, Chiotoroiu AL, Diaconu C. Colorectal cancer: from risk factors to oncogenesis. Medicina (Kaunas) 2023; 59 (09) 1646
- 5 Carr PR, Walter V, Brenner H, Hoffmeister M. Meat subtypes and their association with colorectal cancer: systematic review and meta-analysis. Int J Cancer 2016; 138 (02) 293-302
- 6 Fedirko V, Tramacere I, Bagnardi V. et al. Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies. Ann Oncol 2011; 22 (09) 1958-1972
- 7 Gong J, Hutter C, Baron JA. et al. A pooled analysis of smoking and colorectal cancer: timing of exposure and interactions with environmental factors. Cancer Epidemiol Biomarkers Prev 2012; 21 (11) 1974-1985
- 8 Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA 2021; 325 (07) 669-685
- 9 Kim JC, Bodmer WF. Genotypic and phenotypic characteristics of hereditary colorectal cancer. Ann Coloproctol 2021; 37 (06) 368-381
- 10 Garg P, Malhotra J, Kulkarni P, Horne D, Salgia R, Singhal SS. Emerging therapeutic strategies to overcome drug resistance in cancer cells. Cancers (Basel) 2024; 16 (13) 2478
- 11 Bussmann R, Sharon D. Medicinal plants of the Andes and the Amazon—the magic and medicinal flora of Northern Peru. Ethnobot Res Appl 2018; 15: 1-295
- 12 Li Y-H, Niu Y-B, Sun Y. et al. Role of phytochemicals in colorectal cancer prevention. World J Gastroenterol 2015; 21 (31) 9262-9272
- 13 Zhou E, Rifkin S. Colorectal cancer and diet: risk versus prevention, is diet an intervention?. Gastroenterol Clin North Am 2021; 50 (01) 101-111
- 14 Parmar S, Easwaran H. Genetic and epigenetic dependencies in colorectal cancer development. Gastroenterol Rep (Oxf) 2022; 10: goac035 s
- 15 Al-Sohaily S, Biankin A, Leong R, Kohonen-Corish M, Warusavitarne J. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol 2012; 27 (09) 1423-1431
- 16 Meléndez-Flórez MP, Ortega-Recalde O, Rangel N, Rondón-Lagos M. Chromosomal instability and clonal heterogeneity in breast cancer: from mechanisms to clinical applications. Cancers (Basel) 2025; 17 (07) 1222
- 17 Sharma D, Kushwaha V, Panwar A. et al. Oncogenes and oncogenesis: origin, development, cause, and therapy. In: Upadhyay SK, Singh M, Sharma AK, eds. Anticancer Therapeutics: Bionanotechnology, Nanomedicine and Phytochemicals. Berlin, Boston: De Gruyter; 2024: 31-58
- 18 Peng X, Zhang T, Jia X. et al. Impact of a haplotype (composed of the APC, KRAS, and TP53 genes) on colorectal adenocarcinoma differentiation and patient prognosis. Cancer Genet 2022; 268-269: 115-123
- 19 Catalano T, D'Amico E, Moscatello C. et al. Oxidative distress induces Wnt/β-catenin pathway modulation in colorectal cancer cells: perspectives on APC retained functions. Cancers (Basel) 2021; 13 (23) 6045
- 20 Michel M, Kaps L, Maderer A, Galle PR, Moehler M. The role of p53 dysfunction in colorectal cancer and its implication for therapy. Cancers (Basel) 2021; 13 (10) 2296
- 21 Zhang F, Qiao S. Research progress on the relationship between inflammation and colorectal cancer. Ann Gastroenterol Surg 2021; 6 (02) 204-211
- 22 Muthusami S, Ramachandran IK, Babu KN. et al. Role of inflammation in the development of colorectal cancer. Endocr Metab Immune Disord Drug Targets 2021; 21 (01) 77-90
- 23 Yang J, Xu J, Wang W, Zhang B, Yu X, Shi S. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2023; 8 (01) 210
- 24 Dobre M, Salvi A, Pelisenco IA. et al. Crosstalk between DNA methylation and gene mutations in colorectal cancer. Front Oncol 2021; 11: 697409
- 25 Jia Z, An J, Liu Z, Zhang F. Non-coding RNAs in colorectal cancer: their functions and mechanisms. Front Oncol 2022; 12: 783079
- 26 Zafari N, Khosravi F, Rezaee Z. et al. The role of the tumor microenvironment in colorectal cancer and the potential therapeutic approaches. J Clin Lab Anal 2022; 36 (08) e24585
- 27 Catalano T, Selvaggi F, Cotellese R, Aceto GM. The role of reactive oxygen species in colorectal cancer initiation and progression: perspectives on theranostic approaches. Cancers (Basel) 2025; 17 (05) 752
- 28 De Palma FDE, D'Argenio V, Pol J, Kroemer G, Maiuri MC, Salvatore F. The molecular hallmarks of the serrated pathway in colorectal cancer. Cancers (Basel) 2019; 11 (07) 1017
- 29 Morgan E, Arnold M, Gini A. et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut 2023; 72 (02) 338-344
- 30 Hashem S, Ali TA, Akhtar S. et al. Targeting cancer signaling pathways by natural products: exploring promising anti-cancer agents. Biomed Pharmacother 2022; 150: 113054
- 31 Zughaibi TA, Suhail M, Tarique M, Tabrez S. Targeting PI3K/Akt/mTOR pathway by different flavonoids: a cancer chemopreventive approach. Int J Mol Sci 2021; 22 (22) 12455
- 32 Macharia JM, Mwangi RW, Rozmann N. et al. A systematic review of selected plants and their metabolites with anticolorectal cancer effects. Phytomed Plus 2022; 2 (04) 100332
- 33 De S, Paul S, Manna A. et al. Phenolic phytochemicals for prevention and treatment of colorectal cancer: a critical evaluation of in vivo studies. Cancers (Basel) 2023; 15 (03) 993
- 34 Liang Z, Xie H, Shen W. et al. The synergism of natural compounds and conventional therapeutics against colorectal cancer progression and metastasis. Front Biosci (Landmark Ed) 2022; 27 (09) 263
- 35 Cuevas-Cianca SI, Romero-Castillo C, Gálvez-Romero JL, Juárez ZN, Hernández LR. Antioxidant and anti-inflammatory compounds from edible plants with anti-cancer activity and their potential use as drugs. Molecules 2023; 28 (03) 1488
- 36 Lee DY, Song MY, Kim EH. Role of oxidative stress and Nrf2/KEAP1 signaling in colorectal cancer: mechanisms and therapeutic perspectives with phytochemicals. Antioxidants 2021; 10 (05) 743
- 37 Wang M, Liu X, Chen T. et al. Inhibition and potential treatment of colorectal cancer by natural compounds via various signaling pathways. Front Oncol 2022; 12: 956793
- 38 Zhao H, Ming T, Tang S. et al. Wnt signaling in colorectal cancer: pathogenic role and therapeutic target. Mol Cancer 2022; 21 (01) 144
- 39 Oliveira LFS, Predes D, Borges HL, Abreu JG. Therapeutic potential of naturally occurring small molecules to target the Wnt/β-catenin signaling pathway in colorectal cancer. Cancers (Basel) 2022; 14 (02) 403
- 40 Mokra D, Joskova M, Mokry J. Therapeutic effects of green tea polyphenol (‒)-epigallocatechin-3-gallate (EGCG) in relation to molecular pathways controlling inflammation, oxidative stress, and apoptosis. Int J Mol Sci 2022; 24 (01) 340
- 41 Leiphrakpam PD, Are C. PI3K/Akt/mTOR signaling pathway as a target for colorectal cancer treatment. Int J Mol Sci 2024; 25 (06) 3178
- 42 Liu ZB, Zhang T, Ye X. et al. Natural substances derived from herbs or plants are promising sources of anticancer agents against colorectal cancer via triggering apoptosis. J Pharm Pharmacol 2022; 74 (02) 162-178
- 43 Vaali-Mohammed MA, Nazar A, Meeramaideen M, Khan S. Natural and synthetic compounds against colorectal cancer: an update of preclinical studies in Saudi Arabia. Curr Oncol 2025; 32 (10) 546
- 44 Pavithra R, Khan M, Khan M. Recent advancements in natural compounds for cancer therapy and prevention. Phytochem Rev 2024; 23: 1835-1859
- 45 Hawthorne B, Lund K, Freggiaro S, Kaga R, Meng J. The mechanism of the cytotoxic effect of Panax notoginseng extracts on prostate cancer cells. Biomed Pharmacother 2022; 149: 112887
- 46 Peng BY, Singh AK, Chan CH. et al. AGA induces sub-G1 cell cycle arrest and apoptosis in human colon cancer cells through p53-independent/p53-dependent pathway. BMC Cancer 2023; 23 (01) 1
- 47 El-Wetidy MS, Ahmad R, Rady I. et al. Urolithin A induces cell cycle arrest and apoptosis by inhibiting Bcl-2, increasing p53-p21 proteins and reactive oxygen species production in colorectal cancer cells. Cell Stress Chaperones 2021; 26 (03) 473-493
- 48 Kangra K, Kakkar S, Mittal V. et al. Incredible use of plant-derived bioactives as anticancer agents. RSC Adv 2025; 15 (03) 1721-1746
- 49 Zhang T, Ma C, Zhang Z, Zhang H, Hu H. NF-κB signaling in inflammation and cancer. MedComm 2021; 2 (04) 618-653
- 50 Pandey P, Lakhanpal S, Mahmood D. et al. Recent update of natural compounds as HIF-1α inhibitors in colorectal carcinoma. Drug Des Devel Ther 2025; 19: 2017-2034
- 51 Mo Y, Wu S, Liu Y, Liang Y, Cai Z, Liang L. LRPPRC promotes the progression of colorectal cancer via HIF-1ꭤ/VEGF-meditated angiogenesis. Pathol Res Pract 2025; 275: 156223
- 52 Long J, Guan P, Hu X. et al. Natural polyphenols as targeted modulators in colon cancer: molecular mechanisms and applications. Front Immunol 2021; 12: 635484
- 53 Wang X, Wang L, Ke L. Targeting microRNA-143 in colorectal cancer: advances in molecular biosciences for biomarker-based diagnostics, therapeutic strategies, and drug resistance prediction. Front Mol Biosci 2025; 12: 1679533
- 54 Chen J, Xu T, Chen C. The critical roles of miR-21 in anti-cancer effects of curcumin. Ann Transl Med 2015; 3 (21) 330
- 55 Wong CC, Yu J. Gut microbiota in colorectal cancer development and therapy. Nat Rev Clin Oncol 2023; 20 (07) 429-452
- 56 Han X, Guo L, Jiang X, Wang Y, Wang Z, Li D. Curcumin inhibits cell viability by inducing apoptosis and autophagy in human colon cancer cells. Proceed Anticancer Res 2019; 3: 21-25
- 57 Yang Z, Zhao R, Gao W. The effects of curcumin on the biological behavior of colorectal cancer cells through the JAK/STAT3 and RAS/MAPK/NF-κB pathways. Invest Clin 2022; 63 (04) 353-362
- 58 Villegas I, Sánchez-Fidalgo S, de la Lastra CA. Chemopreventive effect of dietary curcumin on inflammation-induced colorectal carcinogenesis in mice. Mol Nutr Food Res 2011; 55 (02) 259-267
- 59 Deng W, Xiong X, Lu M. et al. Curcumin suppresses colorectal tumorigenesis through restoring the gut microbiota and metabolites. BMC Cancer 2024; 24 (01) 1141
- 60 Jannati M, Allahyari A, Kamandi M. et al. Evaluation of nano-curcumin oral formulation efficacy as an adjuvant treatment in metastatic colorectal patients. J Pharm Care 2025; 13 (01)
- 61 Kim DC, Ku SK, Bae JS. Anticoagulant activities of curcumin and its derivative. BMB Rep 2012; 45 (04) 221-226
- 62 Ojo OA, Adeyemo TR, Rotimi D. et al. Anticancer properties of curcumin against colorectal cancer: a review. Front Oncol 2022; 12: 881641
- 63 Kroon MAGM, van Laarhoven HWM, Swart EL, van Tellingen O, Kemper EM. A pharmacokinetic study and critical reappraisal of curcumin formulations enhancing bioavailability. iScience 2025; 28 (06) 112575
- 64 Almatroodi SAA, A. AlsahliM, SM AljohaniA. et al. Potential therapeutic targets of resveratrol, a plant polyphenol, and its role in the therapy of various types of cancer. Molecules 2022; 27 (09) 2665
- 65 Gong WH, Zhao N, Zhang ZM, Zhang YX, Yan L, Li JB. The inhibitory effect of resveratrol on COX-2 expression in human colorectal cancer: a promising therapeutic strategy. Eur Rev Med Pharmacol Sci 2017; 21 (05) 1136-1143
- 66 Wang J, Zhang Z, Fang A. et al. Resveratrol attenuates inflammatory bowel disease in mice by regulating SUMO1. Biol Pharm Bull 2020; 43 (03) 450-457
- 67 Brockmueller A, Buhrmann C, Shayan P, Shakibaei M. Resveratrol induces apoptosis by modulating the reciprocal crosstalk between p53 and Sirt-1 in the CRC tumor microenvironment. Front Immunol 2023; 14: 1225530
- 68 Tezerji S, Abdolazimi H, Fallah A, Talaei B. The effect of resveratrol and quercetin intervention on azoxymethane-induced colon cancer in Rats model. Clin Nutr Open Sci 2022; 45: 91-102
- 69 Samadi M, Daryanoosh F, Mojtahedi Z. et al. Resistance training and resveratrol supplementation improve cancer cachexia and tumor volume in muscle tissue of male mice bearing colon cancer CT26 cell tumors. Cell Biochem Biophys 2025; 83 (01) 619-631
- 70 Howells LM, Berry DP, Elliott PJ. et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics. Cancer Prev Res (Phila) 2011; 4 (09) 1419-1425
- 71 Planas JM, Alfaras I, Colom H, Juan ME. The bioavailability and distribution of trans-resveratrol are constrained by ABC transporters. Arch Biochem Biophys 2012; 527 (02) 67-73
- 72 Ali M, Benfante V, Di Raimondo D, Salvaggio G, Tuttolomondo A, Comelli A. Recent developments in nanoparticle formulations for resveratrol encapsulation as an anticancer agent. Pharmaceuticals (Basel) 2024; 17 (01) 126
- 73 Chiba T, Kimura Y, Suzuki S, Tatefuji T, Umegaki K. Trans-resveratrol enhances the anticoagulant activity of warfarin in a mouse model. J Atheroscler Thromb 2016; 23 (09) 1099-1110
- 74 Chen Y, Wang X-Q, Zhang Q. et al. (-)-Epigallocatechin-3-gallate inhibits colorectal cancer stem cells by suppressing Wnt/β-catenin pathway. Nutrients 2017; 9 (06) 572
- 75 Almatroodi SA, Almatroudi A, Khan AA, Alhumaydhi FA, Alsahli MA, Rahmani AH. Potential therapeutic targets of epigallocatechin gallate (EGCG), the most abundant catechin in green tea, and its role in the therapy of various types of cancer. Molecules 2020; 25 (14) 3146
- 76 Zhong Y, Chiou Y-S, Pan M-H, Ho C-T, Shahidi F. Protective effects of epigallocatechin gallate (EGCG) derivatives on azoxymethane-induced colonic carcinogenesis in mice. J Funct Foods 2012; 4 (01) 323-330
- 77 Ricci-Vitiani L, Lombardi DG, Pilozzi E. et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007; 445 (7123): 111-115
- 78 Md Nesran ZN, Shafie NH, Ishak AH, Mohd Esa N, Ismail A, Md Tohid SF. Induction of endoplasmic reticulum stress pathway by green tea epigallocatechin-3-gallate (EGCG) in colorectal cancer cells: activation of PERK/p-eIF2α/ATF4 and IRE1α . BioMed Res Int 2019; 2019 (01) 3480569
- 79 Sinicrope FA, Viggiano TR, Buttar NS. et al. Randomized phase II trial of polyphenon E versus placebo in patients at high risk of recurrent colonic neoplasia. Cancer Prev Res (Phila) 2021; 14 (05) 573-580
- 80 Ying Z, He T, Wang X. et al. Parallel comparison of 4-1BB or CD28 co-stimulated CD19-targeted CAR-T cells for B cell non-Hodgkin's lymphoma. Mol Ther Oncolytics 2019; 15: 60-68
- 81 Lambert JD, Hong J, Chen D, Lee M-J, Yang CS. Pharmacokinetics of epigallocatechin-3-gallate in mice and enhancement of bioavailability by other dietary factors. Cancer Res 2004; 64 (7, Suppl): 1247-1247
- 82 Guan Y, Zhu H, Lin M, Zhang Y, He Q, Pan J. Preparation and stability evaluation of flexible nanoliposomes co-encapsulated with black wolfberry anthocyanins and EGCG. Lebensm Wiss Technol 2025; 217: 117402
- 83 Bhattacharya S, Sangave PC, Belemkar S, Anjum MM. pH-sensitive nanoparticles of epigallocatechin-3-gallate in enhanced colorectal cancer therapy. Nanomedicine (Lond) 2024; 19 (06) 459-481
- 84 Satoh T, Fujisawa H, Nakamura A, Takahashi N, Watanabe K. Inhibitory effects of eight green tea catechins on cytochrome P450 1A2, 2C9, 2D6, and 3A4 activities. J Pharm Pharm Sci 2016; 19 (02) 188-197
- 85 Umesalma S, Sudhandiran G. Ellagic acid prevents rat colon carcinogenesis induced by 1, 2 dimethyl hydrazine through inhibition of AKT-phosphoinositide-3 kinase pathway. Eur J Pharmacol 2011; 660 (2-3): 249-258
- 86 Umesalma S, Sudhandiran G. Differential inhibitory effects of the polyphenol ellagic acid on inflammatory mediators NF-kappaB, iNOS, COX-2, TNF-alpha, and IL-6 in 1,2-dimethylhydrazine-induced rat colon carcinogenesis. Basic Clin Pharmacol Toxicol 2010; 107 (02) 650-655
- 87 Syed U, Ganapasam S. Beneficial influence of ellagic acid on biochemical indexes associated with experimentally induced colon carcinogenesis. J Cancer Res Ther 2017; 13 (01) 62-68
- 88 Zhao J, Li G, Wei J. et al. Ellagic acid induces cell cycle arrest and apoptosis via the TGF-β1/Smad3 signaling pathway in human colon cancer HCT 116 cells. Oncol Rep 2020; 44 (02) 768-776
- 89 Chauhan A, Yadav M, Chauhan R. et al. Exploring the potential of ellagic acid in gastrointestinal cancer prevention: recent advances and future directions. Oncol Ther 2024; 12 (04) 685-699
- 90 Nuñez-Sánchez MA, González-Sarrías A, García-Villalba R. et al. Gene expression changes in colon tissues from colorectal cancer patients following the intake of an ellagitannin-containing pomegranate extract: a randomized clinical trial. J Nutr Biochem 2017; 42: 126-133
- 91 Shabani M, Bayrami D, Moghadam AA, Jamali Z, Salimi A. Pretreatment of ellagic acid protects ifosfamide-induced acute nephrotoxicity in rat kidneys: a mitochondrial, histopathological and oxidative stress approaches. Toxicol Rep 2023; 10: 441-447
- 92 Sharifi-Rad J, Quispe C, Castillo CMS. et al. Ellagic acid: a review on its natural sources, chemical stability, and therapeutic potential. Oxid Med Cell Longev 2022; 2022: 3848084
- 93 Raya-Morquecho EM, Aguilar-Zarate P, Sepúlveda L. et al. Ellagitannins and their derivatives: a review on the metabolization, absorption, and some benefits related to intestinal health. Microbiol Res (Pavia) 2025; 16 (06) 113
- 94 Sobhy L, Mostafa M, Fathalla Z, Hussein AK. Ellagic acid-loaded chitosan nanoparticles as an approach for mitigating oxidative stress and liver damage in poloxamer-407-induced hyperlipidemia in mice: development and optimization through 3 level full factorial design. Int J Pharm 2025; 677: 125659
- 95 Bracci L, Fabbri A, Del Cornò M, Conti L. Dietary polyphenols: promising adjuvants for colorectal cancer therapies. Cancers (Basel) 2021; 13 (18) 4499
- 96 Mirza MA, Mahmood S, Hilles AR. et al. Quercetin as a therapeutic product: evaluation of its pharmacological action and clinical applications—a review. Pharmaceuticals (Basel) 2023; 16 (11) 1631
- 97 Neamtu AA, Maghiar TA, Alaya A. et al. A comprehensive view on the quercetin impact on colorectal cancer. Molecules 2022; 27 (06) 1873
- 98 Fu L, Zhao L, Li F. et al. Pharmacological mechanism of quercetin in the treatment of colorectal cancer by network pharmacology and molecular simulation. J Biomol Struct Dyn 2024; 42 (13) 7065-7076
- 99 Salehi B, Machin L, Monzote L. et al. Therapeutic potential of quercetin: new insights and perspectives for human health. ACS Omega 2020; 5 (20) 11849-11872
- 100 Rajesh RU, Dhanaraj S. A critical review on quercetin bioflavonoid and its derivatives: scope, synthesis, and biological applications with future prospects. Arab J Chem 2023; 16: 104881
- 101 Liu L, Barber E, Kellow NJ, Williamson G. Improving quercetin bioavailability: a systematic review and meta-analysis of human intervention studies. Food Chem 2025; 477: 143630
- 102 Andres S, Pevny S, Ziegenhagen R. et al. Safety aspects of the use of quercetin as a dietary supplement. Mol Nutr Food Res 2018 62. 01
- 103 Mehrabadi S. Quercetin's potential therapeutic role in human colorectal cancer: an effective strategy for prevention and treatment. Anticancer Agents Med Chem 2025; 25 (17) 1302-1310
- 104 Stabrauskiene J, Kopustinskiene DM, Lazauskas R, Bernatoniene J. Naringin and naringenin: their mechanisms of action and the potential anticancer activities. Biomedicines 2022; 10 (07) 1686
- 105 Frydoonfar HR, McGrath DR, Spigelman AD. The variable effect on proliferation of a colon cancer cell line by the citrus fruit flavonoid naringenin. Colorectal Dis 2003; 5 (02) 149-152
- 106 He J, Zhang HP. Research progress on the anti-tumor effect of naringin. Front Pharmacol 2023; 14: 1217001
- 107 Zamanian MY, Golmohammadi M, Abdullaev B. et al. A narrative review on therapeutic potential of naringenin in colorectal cancer: focusing on molecular and biochemical processes. Cell Biochem Funct 2024; 42 (03) e4011
- 108 Bai Y, Peng W, Yang C. et al; Clinical Trial. Pharmacokinetics and metabolism of naringin and active metabolite naringenin in rats, dogs, humans, and the differences between species. Front Pharmacol 2020; 11: 364
- 109 Zhang G, Sun G, Guan H. et al. Naringenin nanocrystals for improving anti-rheumatoid arthritis activity. Asian J Pharm Sci 2021; 16 (06) 816-825
- 110 Alotaibi F. Naringenin alters the pharmacokinetics of ranolazine in part through the inhibition of cytochrome P450 (3A4) and P-glycoprotein. Future J Pharm Sci 2023; 9 (01) 23
- 111 Kang KA, Piao MJ, Ryu YS. et al. Luteolin induces apoptotic cell death via antioxidant activity in human colon cancer cells. Int J Oncol 2017; 51 (04) 1169-1178
- 112 Jiang J, Zhu F, Zhang H. et al. Luteolin suppresses the growth of colon cancer cells by inhibiting the IL-6/STAT3 signaling pathway. J Gastrointest Oncol 2022; 13 (04) 1722-1732
- 113 Song Y, Yu J, Li L. et al. Luteolin impacts deoxyribonucleic acid repair by modulating the mitogen-activated protein kinase pathway in colorectal cancer. Bioengineered 2022; 13 (04) 10998-11011
- 114 Yao Y, Rao C, Zheng G, Wang S. Luteolin suppresses colorectal cancer cell metastasis via regulation of the miR-384/pleiotrophin axis. Oncol Rep 2019; 42 (01) 131-141
- 115 Liu Y, Lang T, Jin B. et al. Luteolin inhibits colorectal cancer cell epithelial-to-mesenchymal transition by suppressing CREB1 expression revealed by comparative proteomics study. J Proteomics 2017; 161: 1-10
- 116 Xiao B, Qin Y, Ying C. et al. Combination of oncolytic adenovirus and luteolin exerts synergistic antitumor effects in colorectal cancer cells and a mouse model. Mol Med Rep 2017; 16 (06) 9375-9382
- 117 Pandurangan AK, Dharmalingam P, Sadagopan SKA, Ramar M, Munusamy A, Ganapasam S. Luteolin induces growth arrest in colon cancer cells through involvement of Wnt/β-catenin/GSK-3β signaling. J Environ Pathol Toxicol Oncol 2013; 32 (02) 131-139
- 118 Liu F, Guo C, Liu X. et al. Luteolin in inflammatory bowel disease and colorectal cancer: a disease continuum perspective. Curr Issues Mol Biol 2025; 47 (02) 126
- 119 Li X, He X, Chen S. et al. The genotoxicity potential of luteolin is enhanced by CYP1A1 and CYP1A2 in human lymphoblastoid TK6 cells. Toxicol Lett 2021; 344: 58-68
- 120 Liu J, Sun Y, Cheng M. et al. Improving oral bioavailability of luteolin nanocrystals by surface modification of sodium dodecyl sulfate. AAPS PharmSciTech 2021; 22 (03) 133
- 121 Kaci H, Bodnárová S, Fliszár-Nyúl E. et al. Interaction of luteolin, naringenin, and their sulfate and glucuronide conjugates with human serum albumin, cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) enzymes and organic anion transporting polypeptide (OATP1B1 and OATP2B1) transporters. Biomed Pharmacother 2023; 157: 114078
- 122 Lv J, Song X, Luo Z, Huang D, Xiao L, Zou K. Luteolin: exploring its therapeutic potential and molecular mechanisms in pulmonary diseases. Front Pharmacol 2025; 16: 1535555
- 123 Ntalouka F, Tsirivakou A. Luteolin: a promising natural agent in management of pain in chronic conditions. Front Pain Res (Lausanne) 2023; 4: 1114428
- 124 Sha'at F, Pavaloiu R-D, Petrescu M-M. et al. Development of liposomal and polymeric nanocarriers for luteolin delivery: a senolytic-oriented approach. Chemistry Proceedings 2025; 18 (01) 50
- 125 Li Y-R, Yun T-T, Liu S. et al. Analysis of water-soluble bioactive compounds in commonly consumed soymilk in China. J Food Compos Analysis 2016; 46: 29-35
- 126 Shafiee G, Saidijam M, Tavilani H, Ghasemkhani N, Khodadadi I. Genistein induces apoptosis and inhibits proliferation of HT29 colon cancer cells. Int J Mol Cell Med 2016; 5 (03) 178-191
- 127 Tuli HS, Tuorkey MJ, Thakral F. et al. Molecular mechanisms of action of genistein in cancer: recent advances. Front Pharmacol 2019; 10: 1336
- 128 Naponelli V, Piscazzi A, Mangieri D. Cellular and molecular mechanisms modulated by genistein in cancer. Int J Mol Sci 2025; 26 (03) 1114
- 129 Zhu J, Ren J, Tang L. Genistein inhibits invasion and migration of colon cancer cells by recovering WIF1 expression. Mol Med Rep 2018; 17 (05) 7265-7273
- 130 Liu X, Lan Y, Zhang L. et al. Genistein exerts anti-colorectal cancer actions: clinical reports, computational and validated findings. Aging (Albany NY) 2023; 15 (09) 3678-3689
- 131 Qin J, Chen JX, Zhu Z, Teng JA. Genistein inhibits human colorectal cancer growth and suppresses miR-95, Akt and SGK1. Cell Physiol Biochem 2015; 35 (05) 2069-2077
- 132 Pintova S, Dharmupari S, Moshier E, Zubizarreta N, Ang C, Holcombe RF. Genistein combined with FOLFOX or FOLFOX-bevacizumab for the treatment of metastatic colorectal cancer: phase I/II pilot study. Cancer Chemother Pharmacol 2019; 84 (03) 591-598
- 133 Yang Z, Kulkarni K, Zhu W, Hu M. Bioavailability and pharmacokinetics of genistein: mechanistic studies on its ADME. Anticancer Agents Med Chem 2012; 12 (10) 1264-1280
- 134 Ullmann U, Metzner J, Frank T, Cohn W, Riegger C. Safety, tolerability, and pharmacokinetics of single ascending doses of synthetic genistein (Bonistein) in healthy volunteers. Adv Ther 2005; 22 (01) 65-78
- 135 Yeligar R, Sarwa K, Chandrakar M, Jangde M. Nanotechnology-based delivery of genistein to overcome physicochemical hindrance and enhance therapeutic response in skin cancer. Bionanoscience 2023; 13: 1-20
- 136 Ronis MJ. Effects of soy containing diet and isoflavones on cytochrome P450 enzyme expression and activity. Drug Metab Rev 2016; 48 (03) 331-341
- 137 Setchell KD. Assessing risks and benefits of genistein and soy. Environ Health Perspect 2006; 114 (06) A332-A333
- 138 Kamran S, Sinniah A, Abdulghani MAM, Alshawsh MA. Therapeutic potential of certain terpenoids as anticancer agents: a scoping review. Cancers (Basel) 2022; 14 (05) 1100
- 139 Pandey P, Verma M, Sanghvi G. et al. Plant-derived terpenoids modulating cancer cell metabolism and cross-linked signaling pathways: an updated reviews. Naunyn Schmiedebergs Arch Pharmacol 2025; 398 (07) 8313-8333
- 140 He H. Potential and challenges of terpenoids in cancer therapy: mechanistic review and future perspectives. Theoretical and Natural Science 2025; 75: 13-19
- 141 Niu C, Zhang J, Okolo III PI. Plant terpenoids in combination with conventional therapeutics in colorectal cancer: a promising option. Curr Oncol Rep 2025; 27 (09) 1041-1053
- 142 Sharma SH, Thulasingam S, Nagarajan S. Terpenoids as anti-colon cancer agents—a comprehensive review on its mechanistic perspectives. Eur J Pharmacol 2017; 795: 169-178
- 143 Pereira J, Miguel Castro M, Santos F. et al. Selective terpene based therapeutic deep eutectic systems against colorectal cancer. Eur J Pharm Biopharm 2022; 175: 13-26
- 144 Kaspute G, Ivaskiene T, Ramanavicius A, Ramanavicius S, Prentice U. Terpenes and essential oils in pharmaceutics: applications as therapeutic agents and penetration enhancers with advanced delivery systems for improved stability and bioavailability. Pharmaceutics 2025; 17 (06) 793
- 145 Kohlert C, van Rensen I, März R, Schindler G, Graefe EU, Veit M. Bioavailability and pharmacokinetics of natural volatile terpenes in animals and humans. Planta Med 2000; 66 (06) 495-505
- 146 Masyita A, Mustika Sari R, Dwi Astuti A. et al. Terpenes and terpenoids as main bioactive compounds of essential oils, their roles in human health and potential application as natural food preservatives. Food Chem X 2022; 13: 100217
- 147 Ajaghaku D, Chinwuba P. Plant-drug interactions: mechanisms and clinical implications of cytochrome P450 modulation by common phytochemicals. J Adv Med Pharm Sci 2025; 27: 44-66
- 148 Lin F, Hu Y, Zhang Y, Zhao L, Zhong D, Liu J. Predicting food-drug interactions between piperine and CYP3A4 substrate drugs using PBPK modeling. Int J Mol Sci 2024; 25 (20) 10955
- 149 Gao F-H, Hu X-H, Li W. et al. Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc. BMC Cancer 2010; 10 (01) 610
- 150 Ren CM, Li Y, Chen QZ. et al. Oridonin inhibits the proliferation of human colon cancer cells by upregulating BMP7 to activate p38 MAPK. Oncol Rep 2016; 35 (05) 2691-2698
- 151 Chruścik A, Gopalan V, Lam AK. The clinical and biological roles of transforming growth factor beta in colon cancer stem cells: a systematic review. Eur J Cell Biol 2018; 97 (01) 15-22
- 152 Bu H-Q, Shen F, Cui J. The inhibitory effect of oridonin on colon cancer was mediated by deactivation of TGF-β1/Smads-PAI-1 signaling pathway in vitro and vivo. OncoTargets Ther 2019; 12: 7467-7476
- 153 Liu R-X, Ma Y, Hu X-L. et al. Anticancer effects of oridonin on colon cancer are mediated via BMP7/p38 MAPK/p53 signaling. Int J Oncol 2018; 53 (05) 2091-2101
- 154 Chen F, Liao J, Wu P. et al. Oridonin inhibits the occurrence and development of colorectal cancer by reversing the Warburg effect via reducing PKM2 dimer formation and preventing its entry into the nucleus. Eur J Pharmacol 2023; 954: 175856
- 155 Li X, Zhang C-T, Ma W, Xie X, Huang Q. Oridonin: a review of its pharmacology, pharmacokinetics and toxicity. Front Pharmacol 2021; 12: 645824
- 156 Xu W, Sun J, Zhang TT. et al. Pharmacokinetic behaviors and oral bioavailability of oridonin in rat plasma. Acta Pharmacol Sin 2006; 27 (12) 1642-1646
- 157 Shi C, Zhang L, Hu P. Oridonin-loaded liposomes targeting lung cancer: formulation and delivery in vitro and in vivo. Drug Dev Ind Pharm 2025; 11/30: 1-17
- 158 Liu J, Zhang N, Li N, Fan X, Li Y. Influence of verapamil on the pharmacokinetics of oridonin in rats. Pharm Biol 2019; 57 (01) 787-791
- 159 Zhang Y, Wang S, Dai M, Nai J, Zhu L, Sheng H. Solubility and bioavailability enhancement of oridonin: a review. Molecules 2020; 25 (02) 332
- 160 Srivastava G, Mukherjee E, Mittal R, Ganjewala D. Geraniol and citral: recent developments in their anticancer credentials opening new vistas in complementary cancer therapy. Z Naturforsch C J Biosci 2024; 79 (7-8): 163-177
- 161 Sheikh BY, Sarker MMR, Kamarudin MNA, Mohan G. Antiproliferative and apoptosis inducing effects of citral via p53 and ROS-induced mitochondrial-mediated apoptosis in human colorectal HCT116 and HT29 cell lines. Biomed Pharmacother 2017; 96: 834-846
- 162 Sadati S, Khalaji A, Bonyad A. et al. NF-κB and apoptosis: colorectal cancer progression and novel strategies for treatment. Eur J Med Res 2025; 30 (01) 616
- 163 Chaouki W, Leger DY, Liagre B, Beneytout J-L, Hmamouchi M. Citral inhibits cell proliferation and induces apoptosis and cell cycle arrest in MCF-7 cells. Fundam Clin Pharmacol 2009; 23 (05) 549-556
- 164 Solon IG, Santos WS, Branco LGS. Citral as an anti-inflammatory agent: mechanisms, therapeutic potential, and perspectives. Pharmacological Research - Natural Products 2025; 7: 100253
- 165 Feng S, Sheng J, Yu J, Lin Y, Shao P. Enhancing acid stability of citral through internal structure modulation in nanostructured lipid carriers with solid lipids and phospholipids. Food Res Int 2024; 182: 114148
- 166 Heydorn S, Menné T, Andersen KE. et al. Citral a fragrance allergen and irritant. Contact Dermatitis 2003; 49 (01) 32-36
- 167 Gupta P, Patel DK, Gupta VK, Pal A, Tandon S, Darokar MP. Citral, a monoterpenoid aldehyde interacts synergistically with norfloxacin against methicillin resistant Staphylococcus aureus. Phytomedicine 2017; 34: 85-96
- 168 Hwang S, Jo M, Hong JE, Park CO, Lee CG, Rhee KJ. Protective effects of zerumbone on colonic tumorigenesis in enterotoxigenic Bacteroides fragilis (ETBF)-colonized AOM/DSS BALB/c mice. Int J Mol Sci 2020; 21 (03) 857
- 169 Hosseini N, Khoshnazar A, Saidijam M. et al. Zerumbone suppresses human colorectal cancer invasion and metastasis via modulation of FAk/PI3k/NFκB-uPA pathway. Nutr Cancer 2019; 71 (01) 159-171
- 170 Girisa S, Shabnam B, Monisha J. et al. Potential of zerumbone as an anti-cancer agent. Molecules 2019; 24 (04) 734
- 171 Housseau F, Wu S, Wick EC. et al. Redundant innate and adaptive sources of IL17 production drive colon tumorigenesis. Cancer Res 2016; 76 (08) 2115-2124
- 172 Singh SP, Nongalleima K, Singh NI. et al. Zerumbone reduces proliferation of HCT116 colon cancer cells by inhibition of TNF-alpha. Sci Rep 2018; 8 (01) 4090
- 173 Nobari S, Shojaeian A, Jalilian FA, Kalvandi G, Amini R. Modulation of the tumor microenvironment by zerumbone and 5-fluorouracil in colorectal cancer by target in cancer-associated fibroblasts. Discov Oncol 2025; 16 (01) 505
- 174 Ibáñez MD, Sánchez-Ballester NM, Blázquez MA. Healthy zerumbone: from natural sources to strategies to improve its bioavailability and oral administration. Plants 2022; 12 (01) 5
- 175 Kesharwani SS, Bhat GJ. Formulation and nanotechnology-based approaches for solubility and bioavailability enhancement of zerumbone. Medicina (Kaunas) 2020; 56 (11) 557
- 176 Ashraf SM, Sebastian J, Rathinasamy K. Zerumbone, a cyclic sesquiterpene, exerts antimitotic activity in HeLa cells through tubulin binding and exhibits synergistic activity with vinblastine and paclitaxel. Cell Prolif 2019; 52 (02) e12558
- 177 Aggarwal B, Prasad S, Sung B, Krishnan S, Guha S. Prevention and treatment of colorectal cancer by natural agents from mother nature. Curr Colorectal Cancer Rep 2013; 9 (01) 37-56
- 178 Kim YO, Park HW, Kim JH, Lee JY, Moon SH, Shin CS. Anti-cancer effect and structural characterization of endo-polysaccharide from cultivated mycelia of Inonotus obliquus. Life Sci 2006; 79 (01) 72-80
- 179 Kang J-H, Jang J-E, Mishra SK. et al. Ergosterol peroxide from Chaga mushroom (Inonotus obliquus) exhibits anti-cancer activity by down-regulation of the β-catenin pathway in colorectal cancer. J Ethnopharmacol 2015; 173: 303-312
- 180 Kobori M, Yoshida M, Ohnishi-Kameyama M, Shinmoto H. Ergosterol peroxide from an edible mushroom suppresses inflammatory responses in RAW264.7 macrophages and growth of HT29 colon adenocarcinoma cells. Br J Pharmacol 2007; 150 (02) 209-219
- 181 He L, Shi W, Liu X, Zhao X, Zhang Z. Anticancer action and mechanism of ergosterol peroxide from Paecilomyces cicadae fermentation broth. Int J Mol Sci 2018; 19 (12) 3935
- 182 Ling T, Arroyo-Cruz LV, Smither WR, Seighman EK, Martínez-Montemayor MM, Rivas F. Early preclinical studies of ergosterol peroxide and biological evaluation of its derivatives. ACS Omega 2024; 9 (35) 37117-37127
- 183 Rangsinth P, Sharika R, Pattarachotanant N. et al. Potential beneficial effects and pharmacological properties of ergosterol, a common bioactive compound in edible mushrooms. Foods 2023; 12 (13) 2529
- 184 Lee J-S, Ma C-M, Park D-K, Yoshimi Y, Hatanaka M, Hattori M. Transformation of ergosterol peroxide to cytotoxic substances by rat intestinal bacteria. Biol Pharm Bull 2008; 31 (05) 949-954
- 185 Go R-E, Hwang K-A, Park G-T. et al. Effects of microalgal polyunsaturated fatty acid oil on body weight and lipid accumulation in the liver of C57BL/6 mice fed a high fat diet. J Biomed Res 2016; 30 (03) 234-242
- 186 Liu G, Tang J, Zhou J, Dong M. Short-chain fatty acids play a positive role in colorectal cancer. Discov Oncol 2024; 15 (01) 425
- 187 Tojjari A, Choucair K, Sadeghipour A, Saeed A, Saeed A. Anti-inflammatory and immune properties of polyunsaturated fatty acids (PUFAs) and their impact on colorectal cancer (CRC) prevention and treatment. Cancers (Basel) 2023; 15 (17) 4294
- 188 Hoxha M, Zappacosta B. A review on the role of fatty acids in colorectal cancer progression. Front Pharmacol 2022; 13: 1032806
- 189 Schön C, Micka A, Gourineni V, Bosi R. Superior bioavailability of EPA and DHA from a L-lysine salt formulation: a randomized, three-way crossover study. Food Nutr Res 2024 68.
- 190 Song M, Lee I-M, Manson JE. et al; VITAL Research Group. Effect of supplementation with marine ω-3 fatty acid on risk of colorectal adenomas and serrated polyps in the US general population: a prespecified ancillary study of a randomized clinical trial. JAMA Oncol 2020; 6 (01) 108-115
- 191 Irún P, Lanas A, Piazuelo E. Omega-3 polyunsaturated fatty acids and their bioactive metabolites in gastrointestinal malignancies related to unresolved inflammation. A review. Front Pharmacol 2019; 10: 852
- 192 Nana G, Mitra S, Watson H. et al. Luminal bioavailability of orally administered ω-3 PUFAs in the distal small intestine, and associated changes to the ileal microbiome, in humans with a temporary ileostomy. J Nutr 2021; 151 (08) 2142-2152
- 193 Ji X, Peng Q, Wang M. Anti-colon-cancer effects of polysaccharides: a mini-review of the mechanisms. Int J Biol Macromol 2018; 114: 1127-1133
- 194 Farhaj S, Agbotui TL, Nirwan JS. et al. Carbohydrate polymer-based targeted pharmaceutical formulations for colorectal cancer: systematic review of the literature. Polysaccharides 2022; 3 (04) 692-714
- 195 Nasr SA, Saad AAE-M. Evaluation of the cytotoxic anticancer effect of polysaccharide of Nepeta septemcrenata. Beni Suef Univ J Basic Appl Sci 2021; 10 (01) 53
- 196 Li Y, Liu L, Niu Y. et al. Modified apple polysaccharide prevents against tumorigenesis in a mouse model of colitis-associated colon cancer: role of galectin-3 and apoptosis in cancer prevention. Eur J Nutr 2012; 51 (01) 107-117
- 197 Fan J, Zhu J, Zhu H, Zhang Y, Xu H. Potential therapeutic target for polysaccharide inhibition of colon cancer progression. Front Med (Lausanne) 2024; 10: 1325491
- 198 Tsuboi K, Shimura T, Masuda N. et al. Galectin-3 expression in colorectal cancer: relation to invasion and metastasis. Anticancer Res 2007; 27 (4B): 2289-2296
- 199 Račić A, Gatarić B, Topić Vučenović V, Stojmenovski A. Polysaccharide-based drug delivery systems in pediatrics: addressing age-specific challenges and therapeutic applications. Polysaccharides 2025; 6 (04) 108
- 200 Yi Y, Wang H-X, He J-R. [Research progresses of pharmacokinetics of polysaccharides] [in Chinese]. Yao Xue Xue Bao 2014; 49 (04) 443-449
- 201 Elfahri KR, Vasiljevic T, Yeager T, Donkor ON. Anti-colon cancer and antioxidant activities of bovine skim milk fermented by selected Lactobacillus helveticus strains. J Dairy Sci 2016; 99 (01) 31-40
- 202 Tanihiro R, Yuki M, Sakano K. et al. Effects of heat-treated Lactobacillus helveticus CP790-fermented milk on gastrointestinal health in healthy adults: a randomized double-blind placebo-controlled trial. Nutrients 2024; 16 (14) 2191
- 203 Ye H, Zhang X, Jiang Y. et al. Comparative peptidomics analysis of fermented milk by Lactobacillus delbrueckii ssp. bulgaricus and Lactobacillus delbrueckii ssp. lactis . Foods 2021; 10 (12) 3028
- 204 Asif M, Yehya AHS, Dahham SS. et al. Establishment of in vitro and in vivo anti-colon cancer efficacy of essential oils containing oleo-gum resin extract of Mesua ferrea. Biomed Pharmacother 2019; 109: 1620-1629
- 205 Ying K, Bai B, Gao X, Xu Y, Wang H, Xie B. Orally administrable therapeutic nanoparticles for the treatment of colorectal cancer. Front Bioeng Biotechnol 2021; 9: 670124
- 206 Zalila-Kolsi I, Dhieb D, Osman HA, Mekideche H. The gut microbiota and colorectal cancer: understanding the link and exploring therapeutic interventions. Biology (Basel) 2025; 14 (03) 251
- 207 Akone SH, Ntie-Kang F, Stuhldreier F. et al. Natural products impacting DNA methyltransferases and histone deacetylases. Front Pharmacol 2020; 11: 992
- 208 Hassan FU, Rehman MS, Khan MS. et al. Curcumin as an alternative epigenetic modulator: mechanism of action and potential effects. Front Genet 2019; 10: 514
- 209 Roy S, Deka D, Kondaveeti SB. et al. An overview of potential of natural compounds to regulate epigenetic modifications in colorectal cancer: a recent update. Epigenetics 2025; 20 (01) 2491316
- 210 Lu W, Zeng R, Pan M. et al. Pharmacokinetics, bioavailability, and tissue distribution of MRTX1133 in rats using UHPLC-MS/MS. Front Pharmacol 2024; 15: 1509319
- 211 Shirsat P, A. RZ, Kashikar R. et al. Subacute toxicity study of the ethanolic extract of Mesua ferrea (L.) flowers in rats. Drug Chem Toxicol 2022; 45 (04) 1570-1577
Address for correspondence
Publication History
Article published online:
29 January 2026
© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
-
References
- 1 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
- 2 Ferlay J, Soerjomataram I, Dikshit R. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136 (05) E359-E386
- 3 Shivshankar S, Patil PS, Deodhar K, Budukh AM. Epidemiology of colorectal cancer: a review with special emphasis on India. Indian J Gastroenterol 2025; 44 (02) 142-153
- 4 Ionescu VA, Gheorghe G, Bacalbasa N, Chiotoroiu AL, Diaconu C. Colorectal cancer: from risk factors to oncogenesis. Medicina (Kaunas) 2023; 59 (09) 1646
- 5 Carr PR, Walter V, Brenner H, Hoffmeister M. Meat subtypes and their association with colorectal cancer: systematic review and meta-analysis. Int J Cancer 2016; 138 (02) 293-302
- 6 Fedirko V, Tramacere I, Bagnardi V. et al. Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies. Ann Oncol 2011; 22 (09) 1958-1972
- 7 Gong J, Hutter C, Baron JA. et al. A pooled analysis of smoking and colorectal cancer: timing of exposure and interactions with environmental factors. Cancer Epidemiol Biomarkers Prev 2012; 21 (11) 1974-1985
- 8 Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA 2021; 325 (07) 669-685
- 9 Kim JC, Bodmer WF. Genotypic and phenotypic characteristics of hereditary colorectal cancer. Ann Coloproctol 2021; 37 (06) 368-381
- 10 Garg P, Malhotra J, Kulkarni P, Horne D, Salgia R, Singhal SS. Emerging therapeutic strategies to overcome drug resistance in cancer cells. Cancers (Basel) 2024; 16 (13) 2478
- 11 Bussmann R, Sharon D. Medicinal plants of the Andes and the Amazon—the magic and medicinal flora of Northern Peru. Ethnobot Res Appl 2018; 15: 1-295
- 12 Li Y-H, Niu Y-B, Sun Y. et al. Role of phytochemicals in colorectal cancer prevention. World J Gastroenterol 2015; 21 (31) 9262-9272
- 13 Zhou E, Rifkin S. Colorectal cancer and diet: risk versus prevention, is diet an intervention?. Gastroenterol Clin North Am 2021; 50 (01) 101-111
- 14 Parmar S, Easwaran H. Genetic and epigenetic dependencies in colorectal cancer development. Gastroenterol Rep (Oxf) 2022; 10: goac035 s
- 15 Al-Sohaily S, Biankin A, Leong R, Kohonen-Corish M, Warusavitarne J. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol 2012; 27 (09) 1423-1431
- 16 Meléndez-Flórez MP, Ortega-Recalde O, Rangel N, Rondón-Lagos M. Chromosomal instability and clonal heterogeneity in breast cancer: from mechanisms to clinical applications. Cancers (Basel) 2025; 17 (07) 1222
- 17 Sharma D, Kushwaha V, Panwar A. et al. Oncogenes and oncogenesis: origin, development, cause, and therapy. In: Upadhyay SK, Singh M, Sharma AK, eds. Anticancer Therapeutics: Bionanotechnology, Nanomedicine and Phytochemicals. Berlin, Boston: De Gruyter; 2024: 31-58
- 18 Peng X, Zhang T, Jia X. et al. Impact of a haplotype (composed of the APC, KRAS, and TP53 genes) on colorectal adenocarcinoma differentiation and patient prognosis. Cancer Genet 2022; 268-269: 115-123
- 19 Catalano T, D'Amico E, Moscatello C. et al. Oxidative distress induces Wnt/β-catenin pathway modulation in colorectal cancer cells: perspectives on APC retained functions. Cancers (Basel) 2021; 13 (23) 6045
- 20 Michel M, Kaps L, Maderer A, Galle PR, Moehler M. The role of p53 dysfunction in colorectal cancer and its implication for therapy. Cancers (Basel) 2021; 13 (10) 2296
- 21 Zhang F, Qiao S. Research progress on the relationship between inflammation and colorectal cancer. Ann Gastroenterol Surg 2021; 6 (02) 204-211
- 22 Muthusami S, Ramachandran IK, Babu KN. et al. Role of inflammation in the development of colorectal cancer. Endocr Metab Immune Disord Drug Targets 2021; 21 (01) 77-90
- 23 Yang J, Xu J, Wang W, Zhang B, Yu X, Shi S. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2023; 8 (01) 210
- 24 Dobre M, Salvi A, Pelisenco IA. et al. Crosstalk between DNA methylation and gene mutations in colorectal cancer. Front Oncol 2021; 11: 697409
- 25 Jia Z, An J, Liu Z, Zhang F. Non-coding RNAs in colorectal cancer: their functions and mechanisms. Front Oncol 2022; 12: 783079
- 26 Zafari N, Khosravi F, Rezaee Z. et al. The role of the tumor microenvironment in colorectal cancer and the potential therapeutic approaches. J Clin Lab Anal 2022; 36 (08) e24585
- 27 Catalano T, Selvaggi F, Cotellese R, Aceto GM. The role of reactive oxygen species in colorectal cancer initiation and progression: perspectives on theranostic approaches. Cancers (Basel) 2025; 17 (05) 752
- 28 De Palma FDE, D'Argenio V, Pol J, Kroemer G, Maiuri MC, Salvatore F. The molecular hallmarks of the serrated pathway in colorectal cancer. Cancers (Basel) 2019; 11 (07) 1017
- 29 Morgan E, Arnold M, Gini A. et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut 2023; 72 (02) 338-344
- 30 Hashem S, Ali TA, Akhtar S. et al. Targeting cancer signaling pathways by natural products: exploring promising anti-cancer agents. Biomed Pharmacother 2022; 150: 113054
- 31 Zughaibi TA, Suhail M, Tarique M, Tabrez S. Targeting PI3K/Akt/mTOR pathway by different flavonoids: a cancer chemopreventive approach. Int J Mol Sci 2021; 22 (22) 12455
- 32 Macharia JM, Mwangi RW, Rozmann N. et al. A systematic review of selected plants and their metabolites with anticolorectal cancer effects. Phytomed Plus 2022; 2 (04) 100332
- 33 De S, Paul S, Manna A. et al. Phenolic phytochemicals for prevention and treatment of colorectal cancer: a critical evaluation of in vivo studies. Cancers (Basel) 2023; 15 (03) 993
- 34 Liang Z, Xie H, Shen W. et al. The synergism of natural compounds and conventional therapeutics against colorectal cancer progression and metastasis. Front Biosci (Landmark Ed) 2022; 27 (09) 263
- 35 Cuevas-Cianca SI, Romero-Castillo C, Gálvez-Romero JL, Juárez ZN, Hernández LR. Antioxidant and anti-inflammatory compounds from edible plants with anti-cancer activity and their potential use as drugs. Molecules 2023; 28 (03) 1488
- 36 Lee DY, Song MY, Kim EH. Role of oxidative stress and Nrf2/KEAP1 signaling in colorectal cancer: mechanisms and therapeutic perspectives with phytochemicals. Antioxidants 2021; 10 (05) 743
- 37 Wang M, Liu X, Chen T. et al. Inhibition and potential treatment of colorectal cancer by natural compounds via various signaling pathways. Front Oncol 2022; 12: 956793
- 38 Zhao H, Ming T, Tang S. et al. Wnt signaling in colorectal cancer: pathogenic role and therapeutic target. Mol Cancer 2022; 21 (01) 144
- 39 Oliveira LFS, Predes D, Borges HL, Abreu JG. Therapeutic potential of naturally occurring small molecules to target the Wnt/β-catenin signaling pathway in colorectal cancer. Cancers (Basel) 2022; 14 (02) 403
- 40 Mokra D, Joskova M, Mokry J. Therapeutic effects of green tea polyphenol (‒)-epigallocatechin-3-gallate (EGCG) in relation to molecular pathways controlling inflammation, oxidative stress, and apoptosis. Int J Mol Sci 2022; 24 (01) 340
- 41 Leiphrakpam PD, Are C. PI3K/Akt/mTOR signaling pathway as a target for colorectal cancer treatment. Int J Mol Sci 2024; 25 (06) 3178
- 42 Liu ZB, Zhang T, Ye X. et al. Natural substances derived from herbs or plants are promising sources of anticancer agents against colorectal cancer via triggering apoptosis. J Pharm Pharmacol 2022; 74 (02) 162-178
- 43 Vaali-Mohammed MA, Nazar A, Meeramaideen M, Khan S. Natural and synthetic compounds against colorectal cancer: an update of preclinical studies in Saudi Arabia. Curr Oncol 2025; 32 (10) 546
- 44 Pavithra R, Khan M, Khan M. Recent advancements in natural compounds for cancer therapy and prevention. Phytochem Rev 2024; 23: 1835-1859
- 45 Hawthorne B, Lund K, Freggiaro S, Kaga R, Meng J. The mechanism of the cytotoxic effect of Panax notoginseng extracts on prostate cancer cells. Biomed Pharmacother 2022; 149: 112887
- 46 Peng BY, Singh AK, Chan CH. et al. AGA induces sub-G1 cell cycle arrest and apoptosis in human colon cancer cells through p53-independent/p53-dependent pathway. BMC Cancer 2023; 23 (01) 1
- 47 El-Wetidy MS, Ahmad R, Rady I. et al. Urolithin A induces cell cycle arrest and apoptosis by inhibiting Bcl-2, increasing p53-p21 proteins and reactive oxygen species production in colorectal cancer cells. Cell Stress Chaperones 2021; 26 (03) 473-493
- 48 Kangra K, Kakkar S, Mittal V. et al. Incredible use of plant-derived bioactives as anticancer agents. RSC Adv 2025; 15 (03) 1721-1746
- 49 Zhang T, Ma C, Zhang Z, Zhang H, Hu H. NF-κB signaling in inflammation and cancer. MedComm 2021; 2 (04) 618-653
- 50 Pandey P, Lakhanpal S, Mahmood D. et al. Recent update of natural compounds as HIF-1α inhibitors in colorectal carcinoma. Drug Des Devel Ther 2025; 19: 2017-2034
- 51 Mo Y, Wu S, Liu Y, Liang Y, Cai Z, Liang L. LRPPRC promotes the progression of colorectal cancer via HIF-1ꭤ/VEGF-meditated angiogenesis. Pathol Res Pract 2025; 275: 156223
- 52 Long J, Guan P, Hu X. et al. Natural polyphenols as targeted modulators in colon cancer: molecular mechanisms and applications. Front Immunol 2021; 12: 635484
- 53 Wang X, Wang L, Ke L. Targeting microRNA-143 in colorectal cancer: advances in molecular biosciences for biomarker-based diagnostics, therapeutic strategies, and drug resistance prediction. Front Mol Biosci 2025; 12: 1679533
- 54 Chen J, Xu T, Chen C. The critical roles of miR-21 in anti-cancer effects of curcumin. Ann Transl Med 2015; 3 (21) 330
- 55 Wong CC, Yu J. Gut microbiota in colorectal cancer development and therapy. Nat Rev Clin Oncol 2023; 20 (07) 429-452
- 56 Han X, Guo L, Jiang X, Wang Y, Wang Z, Li D. Curcumin inhibits cell viability by inducing apoptosis and autophagy in human colon cancer cells. Proceed Anticancer Res 2019; 3: 21-25
- 57 Yang Z, Zhao R, Gao W. The effects of curcumin on the biological behavior of colorectal cancer cells through the JAK/STAT3 and RAS/MAPK/NF-κB pathways. Invest Clin 2022; 63 (04) 353-362
- 58 Villegas I, Sánchez-Fidalgo S, de la Lastra CA. Chemopreventive effect of dietary curcumin on inflammation-induced colorectal carcinogenesis in mice. Mol Nutr Food Res 2011; 55 (02) 259-267
- 59 Deng W, Xiong X, Lu M. et al. Curcumin suppresses colorectal tumorigenesis through restoring the gut microbiota and metabolites. BMC Cancer 2024; 24 (01) 1141
- 60 Jannati M, Allahyari A, Kamandi M. et al. Evaluation of nano-curcumin oral formulation efficacy as an adjuvant treatment in metastatic colorectal patients. J Pharm Care 2025; 13 (01)
- 61 Kim DC, Ku SK, Bae JS. Anticoagulant activities of curcumin and its derivative. BMB Rep 2012; 45 (04) 221-226
- 62 Ojo OA, Adeyemo TR, Rotimi D. et al. Anticancer properties of curcumin against colorectal cancer: a review. Front Oncol 2022; 12: 881641
- 63 Kroon MAGM, van Laarhoven HWM, Swart EL, van Tellingen O, Kemper EM. A pharmacokinetic study and critical reappraisal of curcumin formulations enhancing bioavailability. iScience 2025; 28 (06) 112575
- 64 Almatroodi SAA, A. AlsahliM, SM AljohaniA. et al. Potential therapeutic targets of resveratrol, a plant polyphenol, and its role in the therapy of various types of cancer. Molecules 2022; 27 (09) 2665
- 65 Gong WH, Zhao N, Zhang ZM, Zhang YX, Yan L, Li JB. The inhibitory effect of resveratrol on COX-2 expression in human colorectal cancer: a promising therapeutic strategy. Eur Rev Med Pharmacol Sci 2017; 21 (05) 1136-1143
- 66 Wang J, Zhang Z, Fang A. et al. Resveratrol attenuates inflammatory bowel disease in mice by regulating SUMO1. Biol Pharm Bull 2020; 43 (03) 450-457
- 67 Brockmueller A, Buhrmann C, Shayan P, Shakibaei M. Resveratrol induces apoptosis by modulating the reciprocal crosstalk between p53 and Sirt-1 in the CRC tumor microenvironment. Front Immunol 2023; 14: 1225530
- 68 Tezerji S, Abdolazimi H, Fallah A, Talaei B. The effect of resveratrol and quercetin intervention on azoxymethane-induced colon cancer in Rats model. Clin Nutr Open Sci 2022; 45: 91-102
- 69 Samadi M, Daryanoosh F, Mojtahedi Z. et al. Resistance training and resveratrol supplementation improve cancer cachexia and tumor volume in muscle tissue of male mice bearing colon cancer CT26 cell tumors. Cell Biochem Biophys 2025; 83 (01) 619-631
- 70 Howells LM, Berry DP, Elliott PJ. et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics. Cancer Prev Res (Phila) 2011; 4 (09) 1419-1425
- 71 Planas JM, Alfaras I, Colom H, Juan ME. The bioavailability and distribution of trans-resveratrol are constrained by ABC transporters. Arch Biochem Biophys 2012; 527 (02) 67-73
- 72 Ali M, Benfante V, Di Raimondo D, Salvaggio G, Tuttolomondo A, Comelli A. Recent developments in nanoparticle formulations for resveratrol encapsulation as an anticancer agent. Pharmaceuticals (Basel) 2024; 17 (01) 126
- 73 Chiba T, Kimura Y, Suzuki S, Tatefuji T, Umegaki K. Trans-resveratrol enhances the anticoagulant activity of warfarin in a mouse model. J Atheroscler Thromb 2016; 23 (09) 1099-1110
- 74 Chen Y, Wang X-Q, Zhang Q. et al. (-)-Epigallocatechin-3-gallate inhibits colorectal cancer stem cells by suppressing Wnt/β-catenin pathway. Nutrients 2017; 9 (06) 572
- 75 Almatroodi SA, Almatroudi A, Khan AA, Alhumaydhi FA, Alsahli MA, Rahmani AH. Potential therapeutic targets of epigallocatechin gallate (EGCG), the most abundant catechin in green tea, and its role in the therapy of various types of cancer. Molecules 2020; 25 (14) 3146
- 76 Zhong Y, Chiou Y-S, Pan M-H, Ho C-T, Shahidi F. Protective effects of epigallocatechin gallate (EGCG) derivatives on azoxymethane-induced colonic carcinogenesis in mice. J Funct Foods 2012; 4 (01) 323-330
- 77 Ricci-Vitiani L, Lombardi DG, Pilozzi E. et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007; 445 (7123): 111-115
- 78 Md Nesran ZN, Shafie NH, Ishak AH, Mohd Esa N, Ismail A, Md Tohid SF. Induction of endoplasmic reticulum stress pathway by green tea epigallocatechin-3-gallate (EGCG) in colorectal cancer cells: activation of PERK/p-eIF2α/ATF4 and IRE1α . BioMed Res Int 2019; 2019 (01) 3480569
- 79 Sinicrope FA, Viggiano TR, Buttar NS. et al. Randomized phase II trial of polyphenon E versus placebo in patients at high risk of recurrent colonic neoplasia. Cancer Prev Res (Phila) 2021; 14 (05) 573-580
- 80 Ying Z, He T, Wang X. et al. Parallel comparison of 4-1BB or CD28 co-stimulated CD19-targeted CAR-T cells for B cell non-Hodgkin's lymphoma. Mol Ther Oncolytics 2019; 15: 60-68
- 81 Lambert JD, Hong J, Chen D, Lee M-J, Yang CS. Pharmacokinetics of epigallocatechin-3-gallate in mice and enhancement of bioavailability by other dietary factors. Cancer Res 2004; 64 (7, Suppl): 1247-1247
- 82 Guan Y, Zhu H, Lin M, Zhang Y, He Q, Pan J. Preparation and stability evaluation of flexible nanoliposomes co-encapsulated with black wolfberry anthocyanins and EGCG. Lebensm Wiss Technol 2025; 217: 117402
- 83 Bhattacharya S, Sangave PC, Belemkar S, Anjum MM. pH-sensitive nanoparticles of epigallocatechin-3-gallate in enhanced colorectal cancer therapy. Nanomedicine (Lond) 2024; 19 (06) 459-481
- 84 Satoh T, Fujisawa H, Nakamura A, Takahashi N, Watanabe K. Inhibitory effects of eight green tea catechins on cytochrome P450 1A2, 2C9, 2D6, and 3A4 activities. J Pharm Pharm Sci 2016; 19 (02) 188-197
- 85 Umesalma S, Sudhandiran G. Ellagic acid prevents rat colon carcinogenesis induced by 1, 2 dimethyl hydrazine through inhibition of AKT-phosphoinositide-3 kinase pathway. Eur J Pharmacol 2011; 660 (2-3): 249-258
- 86 Umesalma S, Sudhandiran G. Differential inhibitory effects of the polyphenol ellagic acid on inflammatory mediators NF-kappaB, iNOS, COX-2, TNF-alpha, and IL-6 in 1,2-dimethylhydrazine-induced rat colon carcinogenesis. Basic Clin Pharmacol Toxicol 2010; 107 (02) 650-655
- 87 Syed U, Ganapasam S. Beneficial influence of ellagic acid on biochemical indexes associated with experimentally induced colon carcinogenesis. J Cancer Res Ther 2017; 13 (01) 62-68
- 88 Zhao J, Li G, Wei J. et al. Ellagic acid induces cell cycle arrest and apoptosis via the TGF-β1/Smad3 signaling pathway in human colon cancer HCT 116 cells. Oncol Rep 2020; 44 (02) 768-776
- 89 Chauhan A, Yadav M, Chauhan R. et al. Exploring the potential of ellagic acid in gastrointestinal cancer prevention: recent advances and future directions. Oncol Ther 2024; 12 (04) 685-699
- 90 Nuñez-Sánchez MA, González-Sarrías A, García-Villalba R. et al. Gene expression changes in colon tissues from colorectal cancer patients following the intake of an ellagitannin-containing pomegranate extract: a randomized clinical trial. J Nutr Biochem 2017; 42: 126-133
- 91 Shabani M, Bayrami D, Moghadam AA, Jamali Z, Salimi A. Pretreatment of ellagic acid protects ifosfamide-induced acute nephrotoxicity in rat kidneys: a mitochondrial, histopathological and oxidative stress approaches. Toxicol Rep 2023; 10: 441-447
- 92 Sharifi-Rad J, Quispe C, Castillo CMS. et al. Ellagic acid: a review on its natural sources, chemical stability, and therapeutic potential. Oxid Med Cell Longev 2022; 2022: 3848084
- 93 Raya-Morquecho EM, Aguilar-Zarate P, Sepúlveda L. et al. Ellagitannins and their derivatives: a review on the metabolization, absorption, and some benefits related to intestinal health. Microbiol Res (Pavia) 2025; 16 (06) 113
- 94 Sobhy L, Mostafa M, Fathalla Z, Hussein AK. Ellagic acid-loaded chitosan nanoparticles as an approach for mitigating oxidative stress and liver damage in poloxamer-407-induced hyperlipidemia in mice: development and optimization through 3 level full factorial design. Int J Pharm 2025; 677: 125659
- 95 Bracci L, Fabbri A, Del Cornò M, Conti L. Dietary polyphenols: promising adjuvants for colorectal cancer therapies. Cancers (Basel) 2021; 13 (18) 4499
- 96 Mirza MA, Mahmood S, Hilles AR. et al. Quercetin as a therapeutic product: evaluation of its pharmacological action and clinical applications—a review. Pharmaceuticals (Basel) 2023; 16 (11) 1631
- 97 Neamtu AA, Maghiar TA, Alaya A. et al. A comprehensive view on the quercetin impact on colorectal cancer. Molecules 2022; 27 (06) 1873
- 98 Fu L, Zhao L, Li F. et al. Pharmacological mechanism of quercetin in the treatment of colorectal cancer by network pharmacology and molecular simulation. J Biomol Struct Dyn 2024; 42 (13) 7065-7076
- 99 Salehi B, Machin L, Monzote L. et al. Therapeutic potential of quercetin: new insights and perspectives for human health. ACS Omega 2020; 5 (20) 11849-11872
- 100 Rajesh RU, Dhanaraj S. A critical review on quercetin bioflavonoid and its derivatives: scope, synthesis, and biological applications with future prospects. Arab J Chem 2023; 16: 104881
- 101 Liu L, Barber E, Kellow NJ, Williamson G. Improving quercetin bioavailability: a systematic review and meta-analysis of human intervention studies. Food Chem 2025; 477: 143630
- 102 Andres S, Pevny S, Ziegenhagen R. et al. Safety aspects of the use of quercetin as a dietary supplement. Mol Nutr Food Res 2018 62. 01
- 103 Mehrabadi S. Quercetin's potential therapeutic role in human colorectal cancer: an effective strategy for prevention and treatment. Anticancer Agents Med Chem 2025; 25 (17) 1302-1310
- 104 Stabrauskiene J, Kopustinskiene DM, Lazauskas R, Bernatoniene J. Naringin and naringenin: their mechanisms of action and the potential anticancer activities. Biomedicines 2022; 10 (07) 1686
- 105 Frydoonfar HR, McGrath DR, Spigelman AD. The variable effect on proliferation of a colon cancer cell line by the citrus fruit flavonoid naringenin. Colorectal Dis 2003; 5 (02) 149-152
- 106 He J, Zhang HP. Research progress on the anti-tumor effect of naringin. Front Pharmacol 2023; 14: 1217001
- 107 Zamanian MY, Golmohammadi M, Abdullaev B. et al. A narrative review on therapeutic potential of naringenin in colorectal cancer: focusing on molecular and biochemical processes. Cell Biochem Funct 2024; 42 (03) e4011
- 108 Bai Y, Peng W, Yang C. et al; Clinical Trial. Pharmacokinetics and metabolism of naringin and active metabolite naringenin in rats, dogs, humans, and the differences between species. Front Pharmacol 2020; 11: 364
- 109 Zhang G, Sun G, Guan H. et al. Naringenin nanocrystals for improving anti-rheumatoid arthritis activity. Asian J Pharm Sci 2021; 16 (06) 816-825
- 110 Alotaibi F. Naringenin alters the pharmacokinetics of ranolazine in part through the inhibition of cytochrome P450 (3A4) and P-glycoprotein. Future J Pharm Sci 2023; 9 (01) 23
- 111 Kang KA, Piao MJ, Ryu YS. et al. Luteolin induces apoptotic cell death via antioxidant activity in human colon cancer cells. Int J Oncol 2017; 51 (04) 1169-1178
- 112 Jiang J, Zhu F, Zhang H. et al. Luteolin suppresses the growth of colon cancer cells by inhibiting the IL-6/STAT3 signaling pathway. J Gastrointest Oncol 2022; 13 (04) 1722-1732
- 113 Song Y, Yu J, Li L. et al. Luteolin impacts deoxyribonucleic acid repair by modulating the mitogen-activated protein kinase pathway in colorectal cancer. Bioengineered 2022; 13 (04) 10998-11011
- 114 Yao Y, Rao C, Zheng G, Wang S. Luteolin suppresses colorectal cancer cell metastasis via regulation of the miR-384/pleiotrophin axis. Oncol Rep 2019; 42 (01) 131-141
- 115 Liu Y, Lang T, Jin B. et al. Luteolin inhibits colorectal cancer cell epithelial-to-mesenchymal transition by suppressing CREB1 expression revealed by comparative proteomics study. J Proteomics 2017; 161: 1-10
- 116 Xiao B, Qin Y, Ying C. et al. Combination of oncolytic adenovirus and luteolin exerts synergistic antitumor effects in colorectal cancer cells and a mouse model. Mol Med Rep 2017; 16 (06) 9375-9382
- 117 Pandurangan AK, Dharmalingam P, Sadagopan SKA, Ramar M, Munusamy A, Ganapasam S. Luteolin induces growth arrest in colon cancer cells through involvement of Wnt/β-catenin/GSK-3β signaling. J Environ Pathol Toxicol Oncol 2013; 32 (02) 131-139
- 118 Liu F, Guo C, Liu X. et al. Luteolin in inflammatory bowel disease and colorectal cancer: a disease continuum perspective. Curr Issues Mol Biol 2025; 47 (02) 126
- 119 Li X, He X, Chen S. et al. The genotoxicity potential of luteolin is enhanced by CYP1A1 and CYP1A2 in human lymphoblastoid TK6 cells. Toxicol Lett 2021; 344: 58-68
- 120 Liu J, Sun Y, Cheng M. et al. Improving oral bioavailability of luteolin nanocrystals by surface modification of sodium dodecyl sulfate. AAPS PharmSciTech 2021; 22 (03) 133
- 121 Kaci H, Bodnárová S, Fliszár-Nyúl E. et al. Interaction of luteolin, naringenin, and their sulfate and glucuronide conjugates with human serum albumin, cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) enzymes and organic anion transporting polypeptide (OATP1B1 and OATP2B1) transporters. Biomed Pharmacother 2023; 157: 114078
- 122 Lv J, Song X, Luo Z, Huang D, Xiao L, Zou K. Luteolin: exploring its therapeutic potential and molecular mechanisms in pulmonary diseases. Front Pharmacol 2025; 16: 1535555
- 123 Ntalouka F, Tsirivakou A. Luteolin: a promising natural agent in management of pain in chronic conditions. Front Pain Res (Lausanne) 2023; 4: 1114428
- 124 Sha'at F, Pavaloiu R-D, Petrescu M-M. et al. Development of liposomal and polymeric nanocarriers for luteolin delivery: a senolytic-oriented approach. Chemistry Proceedings 2025; 18 (01) 50
- 125 Li Y-R, Yun T-T, Liu S. et al. Analysis of water-soluble bioactive compounds in commonly consumed soymilk in China. J Food Compos Analysis 2016; 46: 29-35
- 126 Shafiee G, Saidijam M, Tavilani H, Ghasemkhani N, Khodadadi I. Genistein induces apoptosis and inhibits proliferation of HT29 colon cancer cells. Int J Mol Cell Med 2016; 5 (03) 178-191
- 127 Tuli HS, Tuorkey MJ, Thakral F. et al. Molecular mechanisms of action of genistein in cancer: recent advances. Front Pharmacol 2019; 10: 1336
- 128 Naponelli V, Piscazzi A, Mangieri D. Cellular and molecular mechanisms modulated by genistein in cancer. Int J Mol Sci 2025; 26 (03) 1114
- 129 Zhu J, Ren J, Tang L. Genistein inhibits invasion and migration of colon cancer cells by recovering WIF1 expression. Mol Med Rep 2018; 17 (05) 7265-7273
- 130 Liu X, Lan Y, Zhang L. et al. Genistein exerts anti-colorectal cancer actions: clinical reports, computational and validated findings. Aging (Albany NY) 2023; 15 (09) 3678-3689
- 131 Qin J, Chen JX, Zhu Z, Teng JA. Genistein inhibits human colorectal cancer growth and suppresses miR-95, Akt and SGK1. Cell Physiol Biochem 2015; 35 (05) 2069-2077
- 132 Pintova S, Dharmupari S, Moshier E, Zubizarreta N, Ang C, Holcombe RF. Genistein combined with FOLFOX or FOLFOX-bevacizumab for the treatment of metastatic colorectal cancer: phase I/II pilot study. Cancer Chemother Pharmacol 2019; 84 (03) 591-598
- 133 Yang Z, Kulkarni K, Zhu W, Hu M. Bioavailability and pharmacokinetics of genistein: mechanistic studies on its ADME. Anticancer Agents Med Chem 2012; 12 (10) 1264-1280
- 134 Ullmann U, Metzner J, Frank T, Cohn W, Riegger C. Safety, tolerability, and pharmacokinetics of single ascending doses of synthetic genistein (Bonistein) in healthy volunteers. Adv Ther 2005; 22 (01) 65-78
- 135 Yeligar R, Sarwa K, Chandrakar M, Jangde M. Nanotechnology-based delivery of genistein to overcome physicochemical hindrance and enhance therapeutic response in skin cancer. Bionanoscience 2023; 13: 1-20
- 136 Ronis MJ. Effects of soy containing diet and isoflavones on cytochrome P450 enzyme expression and activity. Drug Metab Rev 2016; 48 (03) 331-341
- 137 Setchell KD. Assessing risks and benefits of genistein and soy. Environ Health Perspect 2006; 114 (06) A332-A333
- 138 Kamran S, Sinniah A, Abdulghani MAM, Alshawsh MA. Therapeutic potential of certain terpenoids as anticancer agents: a scoping review. Cancers (Basel) 2022; 14 (05) 1100
- 139 Pandey P, Verma M, Sanghvi G. et al. Plant-derived terpenoids modulating cancer cell metabolism and cross-linked signaling pathways: an updated reviews. Naunyn Schmiedebergs Arch Pharmacol 2025; 398 (07) 8313-8333
- 140 He H. Potential and challenges of terpenoids in cancer therapy: mechanistic review and future perspectives. Theoretical and Natural Science 2025; 75: 13-19
- 141 Niu C, Zhang J, Okolo III PI. Plant terpenoids in combination with conventional therapeutics in colorectal cancer: a promising option. Curr Oncol Rep 2025; 27 (09) 1041-1053
- 142 Sharma SH, Thulasingam S, Nagarajan S. Terpenoids as anti-colon cancer agents—a comprehensive review on its mechanistic perspectives. Eur J Pharmacol 2017; 795: 169-178
- 143 Pereira J, Miguel Castro M, Santos F. et al. Selective terpene based therapeutic deep eutectic systems against colorectal cancer. Eur J Pharm Biopharm 2022; 175: 13-26
- 144 Kaspute G, Ivaskiene T, Ramanavicius A, Ramanavicius S, Prentice U. Terpenes and essential oils in pharmaceutics: applications as therapeutic agents and penetration enhancers with advanced delivery systems for improved stability and bioavailability. Pharmaceutics 2025; 17 (06) 793
- 145 Kohlert C, van Rensen I, März R, Schindler G, Graefe EU, Veit M. Bioavailability and pharmacokinetics of natural volatile terpenes in animals and humans. Planta Med 2000; 66 (06) 495-505
- 146 Masyita A, Mustika Sari R, Dwi Astuti A. et al. Terpenes and terpenoids as main bioactive compounds of essential oils, their roles in human health and potential application as natural food preservatives. Food Chem X 2022; 13: 100217
- 147 Ajaghaku D, Chinwuba P. Plant-drug interactions: mechanisms and clinical implications of cytochrome P450 modulation by common phytochemicals. J Adv Med Pharm Sci 2025; 27: 44-66
- 148 Lin F, Hu Y, Zhang Y, Zhao L, Zhong D, Liu J. Predicting food-drug interactions between piperine and CYP3A4 substrate drugs using PBPK modeling. Int J Mol Sci 2024; 25 (20) 10955
- 149 Gao F-H, Hu X-H, Li W. et al. Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc. BMC Cancer 2010; 10 (01) 610
- 150 Ren CM, Li Y, Chen QZ. et al. Oridonin inhibits the proliferation of human colon cancer cells by upregulating BMP7 to activate p38 MAPK. Oncol Rep 2016; 35 (05) 2691-2698
- 151 Chruścik A, Gopalan V, Lam AK. The clinical and biological roles of transforming growth factor beta in colon cancer stem cells: a systematic review. Eur J Cell Biol 2018; 97 (01) 15-22
- 152 Bu H-Q, Shen F, Cui J. The inhibitory effect of oridonin on colon cancer was mediated by deactivation of TGF-β1/Smads-PAI-1 signaling pathway in vitro and vivo. OncoTargets Ther 2019; 12: 7467-7476
- 153 Liu R-X, Ma Y, Hu X-L. et al. Anticancer effects of oridonin on colon cancer are mediated via BMP7/p38 MAPK/p53 signaling. Int J Oncol 2018; 53 (05) 2091-2101
- 154 Chen F, Liao J, Wu P. et al. Oridonin inhibits the occurrence and development of colorectal cancer by reversing the Warburg effect via reducing PKM2 dimer formation and preventing its entry into the nucleus. Eur J Pharmacol 2023; 954: 175856
- 155 Li X, Zhang C-T, Ma W, Xie X, Huang Q. Oridonin: a review of its pharmacology, pharmacokinetics and toxicity. Front Pharmacol 2021; 12: 645824
- 156 Xu W, Sun J, Zhang TT. et al. Pharmacokinetic behaviors and oral bioavailability of oridonin in rat plasma. Acta Pharmacol Sin 2006; 27 (12) 1642-1646
- 157 Shi C, Zhang L, Hu P. Oridonin-loaded liposomes targeting lung cancer: formulation and delivery in vitro and in vivo. Drug Dev Ind Pharm 2025; 11/30: 1-17
- 158 Liu J, Zhang N, Li N, Fan X, Li Y. Influence of verapamil on the pharmacokinetics of oridonin in rats. Pharm Biol 2019; 57 (01) 787-791
- 159 Zhang Y, Wang S, Dai M, Nai J, Zhu L, Sheng H. Solubility and bioavailability enhancement of oridonin: a review. Molecules 2020; 25 (02) 332
- 160 Srivastava G, Mukherjee E, Mittal R, Ganjewala D. Geraniol and citral: recent developments in their anticancer credentials opening new vistas in complementary cancer therapy. Z Naturforsch C J Biosci 2024; 79 (7-8): 163-177
- 161 Sheikh BY, Sarker MMR, Kamarudin MNA, Mohan G. Antiproliferative and apoptosis inducing effects of citral via p53 and ROS-induced mitochondrial-mediated apoptosis in human colorectal HCT116 and HT29 cell lines. Biomed Pharmacother 2017; 96: 834-846
- 162 Sadati S, Khalaji A, Bonyad A. et al. NF-κB and apoptosis: colorectal cancer progression and novel strategies for treatment. Eur J Med Res 2025; 30 (01) 616
- 163 Chaouki W, Leger DY, Liagre B, Beneytout J-L, Hmamouchi M. Citral inhibits cell proliferation and induces apoptosis and cell cycle arrest in MCF-7 cells. Fundam Clin Pharmacol 2009; 23 (05) 549-556
- 164 Solon IG, Santos WS, Branco LGS. Citral as an anti-inflammatory agent: mechanisms, therapeutic potential, and perspectives. Pharmacological Research - Natural Products 2025; 7: 100253
- 165 Feng S, Sheng J, Yu J, Lin Y, Shao P. Enhancing acid stability of citral through internal structure modulation in nanostructured lipid carriers with solid lipids and phospholipids. Food Res Int 2024; 182: 114148
- 166 Heydorn S, Menné T, Andersen KE. et al. Citral a fragrance allergen and irritant. Contact Dermatitis 2003; 49 (01) 32-36
- 167 Gupta P, Patel DK, Gupta VK, Pal A, Tandon S, Darokar MP. Citral, a monoterpenoid aldehyde interacts synergistically with norfloxacin against methicillin resistant Staphylococcus aureus. Phytomedicine 2017; 34: 85-96
- 168 Hwang S, Jo M, Hong JE, Park CO, Lee CG, Rhee KJ. Protective effects of zerumbone on colonic tumorigenesis in enterotoxigenic Bacteroides fragilis (ETBF)-colonized AOM/DSS BALB/c mice. Int J Mol Sci 2020; 21 (03) 857
- 169 Hosseini N, Khoshnazar A, Saidijam M. et al. Zerumbone suppresses human colorectal cancer invasion and metastasis via modulation of FAk/PI3k/NFκB-uPA pathway. Nutr Cancer 2019; 71 (01) 159-171
- 170 Girisa S, Shabnam B, Monisha J. et al. Potential of zerumbone as an anti-cancer agent. Molecules 2019; 24 (04) 734
- 171 Housseau F, Wu S, Wick EC. et al. Redundant innate and adaptive sources of IL17 production drive colon tumorigenesis. Cancer Res 2016; 76 (08) 2115-2124
- 172 Singh SP, Nongalleima K, Singh NI. et al. Zerumbone reduces proliferation of HCT116 colon cancer cells by inhibition of TNF-alpha. Sci Rep 2018; 8 (01) 4090
- 173 Nobari S, Shojaeian A, Jalilian FA, Kalvandi G, Amini R. Modulation of the tumor microenvironment by zerumbone and 5-fluorouracil in colorectal cancer by target in cancer-associated fibroblasts. Discov Oncol 2025; 16 (01) 505
- 174 Ibáñez MD, Sánchez-Ballester NM, Blázquez MA. Healthy zerumbone: from natural sources to strategies to improve its bioavailability and oral administration. Plants 2022; 12 (01) 5
- 175 Kesharwani SS, Bhat GJ. Formulation and nanotechnology-based approaches for solubility and bioavailability enhancement of zerumbone. Medicina (Kaunas) 2020; 56 (11) 557
- 176 Ashraf SM, Sebastian J, Rathinasamy K. Zerumbone, a cyclic sesquiterpene, exerts antimitotic activity in HeLa cells through tubulin binding and exhibits synergistic activity with vinblastine and paclitaxel. Cell Prolif 2019; 52 (02) e12558
- 177 Aggarwal B, Prasad S, Sung B, Krishnan S, Guha S. Prevention and treatment of colorectal cancer by natural agents from mother nature. Curr Colorectal Cancer Rep 2013; 9 (01) 37-56
- 178 Kim YO, Park HW, Kim JH, Lee JY, Moon SH, Shin CS. Anti-cancer effect and structural characterization of endo-polysaccharide from cultivated mycelia of Inonotus obliquus. Life Sci 2006; 79 (01) 72-80
- 179 Kang J-H, Jang J-E, Mishra SK. et al. Ergosterol peroxide from Chaga mushroom (Inonotus obliquus) exhibits anti-cancer activity by down-regulation of the β-catenin pathway in colorectal cancer. J Ethnopharmacol 2015; 173: 303-312
- 180 Kobori M, Yoshida M, Ohnishi-Kameyama M, Shinmoto H. Ergosterol peroxide from an edible mushroom suppresses inflammatory responses in RAW264.7 macrophages and growth of HT29 colon adenocarcinoma cells. Br J Pharmacol 2007; 150 (02) 209-219
- 181 He L, Shi W, Liu X, Zhao X, Zhang Z. Anticancer action and mechanism of ergosterol peroxide from Paecilomyces cicadae fermentation broth. Int J Mol Sci 2018; 19 (12) 3935
- 182 Ling T, Arroyo-Cruz LV, Smither WR, Seighman EK, Martínez-Montemayor MM, Rivas F. Early preclinical studies of ergosterol peroxide and biological evaluation of its derivatives. ACS Omega 2024; 9 (35) 37117-37127
- 183 Rangsinth P, Sharika R, Pattarachotanant N. et al. Potential beneficial effects and pharmacological properties of ergosterol, a common bioactive compound in edible mushrooms. Foods 2023; 12 (13) 2529
- 184 Lee J-S, Ma C-M, Park D-K, Yoshimi Y, Hatanaka M, Hattori M. Transformation of ergosterol peroxide to cytotoxic substances by rat intestinal bacteria. Biol Pharm Bull 2008; 31 (05) 949-954
- 185 Go R-E, Hwang K-A, Park G-T. et al. Effects of microalgal polyunsaturated fatty acid oil on body weight and lipid accumulation in the liver of C57BL/6 mice fed a high fat diet. J Biomed Res 2016; 30 (03) 234-242
- 186 Liu G, Tang J, Zhou J, Dong M. Short-chain fatty acids play a positive role in colorectal cancer. Discov Oncol 2024; 15 (01) 425
- 187 Tojjari A, Choucair K, Sadeghipour A, Saeed A, Saeed A. Anti-inflammatory and immune properties of polyunsaturated fatty acids (PUFAs) and their impact on colorectal cancer (CRC) prevention and treatment. Cancers (Basel) 2023; 15 (17) 4294
- 188 Hoxha M, Zappacosta B. A review on the role of fatty acids in colorectal cancer progression. Front Pharmacol 2022; 13: 1032806
- 189 Schön C, Micka A, Gourineni V, Bosi R. Superior bioavailability of EPA and DHA from a L-lysine salt formulation: a randomized, three-way crossover study. Food Nutr Res 2024 68.
- 190 Song M, Lee I-M, Manson JE. et al; VITAL Research Group. Effect of supplementation with marine ω-3 fatty acid on risk of colorectal adenomas and serrated polyps in the US general population: a prespecified ancillary study of a randomized clinical trial. JAMA Oncol 2020; 6 (01) 108-115
- 191 Irún P, Lanas A, Piazuelo E. Omega-3 polyunsaturated fatty acids and their bioactive metabolites in gastrointestinal malignancies related to unresolved inflammation. A review. Front Pharmacol 2019; 10: 852
- 192 Nana G, Mitra S, Watson H. et al. Luminal bioavailability of orally administered ω-3 PUFAs in the distal small intestine, and associated changes to the ileal microbiome, in humans with a temporary ileostomy. J Nutr 2021; 151 (08) 2142-2152
- 193 Ji X, Peng Q, Wang M. Anti-colon-cancer effects of polysaccharides: a mini-review of the mechanisms. Int J Biol Macromol 2018; 114: 1127-1133
- 194 Farhaj S, Agbotui TL, Nirwan JS. et al. Carbohydrate polymer-based targeted pharmaceutical formulations for colorectal cancer: systematic review of the literature. Polysaccharides 2022; 3 (04) 692-714
- 195 Nasr SA, Saad AAE-M. Evaluation of the cytotoxic anticancer effect of polysaccharide of Nepeta septemcrenata. Beni Suef Univ J Basic Appl Sci 2021; 10 (01) 53
- 196 Li Y, Liu L, Niu Y. et al. Modified apple polysaccharide prevents against tumorigenesis in a mouse model of colitis-associated colon cancer: role of galectin-3 and apoptosis in cancer prevention. Eur J Nutr 2012; 51 (01) 107-117
- 197 Fan J, Zhu J, Zhu H, Zhang Y, Xu H. Potential therapeutic target for polysaccharide inhibition of colon cancer progression. Front Med (Lausanne) 2024; 10: 1325491
- 198 Tsuboi K, Shimura T, Masuda N. et al. Galectin-3 expression in colorectal cancer: relation to invasion and metastasis. Anticancer Res 2007; 27 (4B): 2289-2296
- 199 Račić A, Gatarić B, Topić Vučenović V, Stojmenovski A. Polysaccharide-based drug delivery systems in pediatrics: addressing age-specific challenges and therapeutic applications. Polysaccharides 2025; 6 (04) 108
- 200 Yi Y, Wang H-X, He J-R. [Research progresses of pharmacokinetics of polysaccharides] [in Chinese]. Yao Xue Xue Bao 2014; 49 (04) 443-449
- 201 Elfahri KR, Vasiljevic T, Yeager T, Donkor ON. Anti-colon cancer and antioxidant activities of bovine skim milk fermented by selected Lactobacillus helveticus strains. J Dairy Sci 2016; 99 (01) 31-40
- 202 Tanihiro R, Yuki M, Sakano K. et al. Effects of heat-treated Lactobacillus helveticus CP790-fermented milk on gastrointestinal health in healthy adults: a randomized double-blind placebo-controlled trial. Nutrients 2024; 16 (14) 2191
- 203 Ye H, Zhang X, Jiang Y. et al. Comparative peptidomics analysis of fermented milk by Lactobacillus delbrueckii ssp. bulgaricus and Lactobacillus delbrueckii ssp. lactis . Foods 2021; 10 (12) 3028
- 204 Asif M, Yehya AHS, Dahham SS. et al. Establishment of in vitro and in vivo anti-colon cancer efficacy of essential oils containing oleo-gum resin extract of Mesua ferrea. Biomed Pharmacother 2019; 109: 1620-1629
- 205 Ying K, Bai B, Gao X, Xu Y, Wang H, Xie B. Orally administrable therapeutic nanoparticles for the treatment of colorectal cancer. Front Bioeng Biotechnol 2021; 9: 670124
- 206 Zalila-Kolsi I, Dhieb D, Osman HA, Mekideche H. The gut microbiota and colorectal cancer: understanding the link and exploring therapeutic interventions. Biology (Basel) 2025; 14 (03) 251
- 207 Akone SH, Ntie-Kang F, Stuhldreier F. et al. Natural products impacting DNA methyltransferases and histone deacetylases. Front Pharmacol 2020; 11: 992
- 208 Hassan FU, Rehman MS, Khan MS. et al. Curcumin as an alternative epigenetic modulator: mechanism of action and potential effects. Front Genet 2019; 10: 514
- 209 Roy S, Deka D, Kondaveeti SB. et al. An overview of potential of natural compounds to regulate epigenetic modifications in colorectal cancer: a recent update. Epigenetics 2025; 20 (01) 2491316
- 210 Lu W, Zeng R, Pan M. et al. Pharmacokinetics, bioavailability, and tissue distribution of MRTX1133 in rats using UHPLC-MS/MS. Front Pharmacol 2024; 15: 1509319
- 211 Shirsat P, A. RZ, Kashikar R. et al. Subacute toxicity study of the ethanolic extract of Mesua ferrea (L.) flowers in rats. Drug Chem Toxicol 2022; 45 (04) 1570-1577