Keywords
Curcuma longa.
- Zingiberaceae - turmeric - curcumin - antitumor molecular mechanism - epigenetics - tumor immunity - drug delivery system
Abbreviations
bFGF:
basic fibroblast growth tactor
COX-2:
cyclooxygenase-2
CSCs:
cancer stem cells
CUR-PEG:
combination of curcumin-polyethylene glycol conjugate
DNAMT3A:
DNA methyltransferase 3A
ERK:
extracellular-signal-regulated kinases
GRB2:
growth factor receptor binding protein 2
HMGB1:
high mobility group protein B1
ICAM-1:
intercellular adhesion molecule-
ICs:
immune checkpoints
IL-6:
interleukin-6
IL-8:
interleukin-8
JAK/STAT:
Janus Kinase/Signal transducers and activators of transcription
Ln-cRNA:
long non-coding RNAs
LNRs:
Lin12/Notch repeats
MARCKS:
myristoylated alanine-rich protein kinase C substrate
MDR:
multidrug resistance
miRNAs:
MicroRNAs
MMP:
matrix metalloproteinases
MMP-9:
matrix metalloproteinase-9
mTOR:
mammalian target of rapamycin
PD-1:
programmed cell death protein 1
PDR:
prodrug resistance
PI3K:
phosphatidylinositide-3-kinases
PKC:
protein kinase C
PPNMs:
prepared a new type of nano micelles
PRMT5:
protein concentrations of arginine methyltransferase 5
RT-PCR:
reverse transcription polymerase chain reaction
TGF-β1:
transforming growth factor-β1
TLR2:
Toll-like receptor 2
TLR4:
Toll-like receptor 4
TNF-α
:
tumor necrosis factor-α
VCR:
vincristine-resistant
VEGF-D:
vascular endothelial growth factor D
VEGFV:
vascular endothelial growth factor
Introduction
Cancer is a severe threat to human health, and its prevention and treatment have become a global problem [1]. As a worldwide public health problem, the number of people dying from cancer has reached 900 000 yearly [1], [2]. Radiotherapy and chemotherapy are common treatments for cancer, but while killing cancer cells, they also damage the bodyʼs normal cells [3]. Despite the significant progress in oncology treatment, the morbidity and mortality of malignant tumors remain high [1], [2]. Therefore, searching for more efficient and less toxic therapeutic strategies for tumor treatment remains the focus of current research.
Curcumin is a flavin pigment extracted from the rhizome of Curcuma longa L. (Zingiberaceae), which is a lipid-soluble polyphenol with unsaturated aliphatic and aromatic groups in the main chain, molecular formula C21H20O6, chemical name 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-one ([Fig. 1]). Curcumin is a hydrophobic polyphenol soluble in ethanol, acetone, and dimethyl sulfoxide. It has various biological and pharmacological activities for treating tumors, diabetes, inflammation, neurodegenerative diseases, cardiovascular diseases, metabolic syndrome, and liver diseases [4]. In recent years, the application of curcumin in antitumor treatment has received extensive attention from researchers. Its actions and mechanisms mainly include inhibition of tumor invasion and migration, induction of tumor cell apoptosis, and inhibition of various cell signaling pathways. Other
studies have shown that the biological activity of curcumin in the organism may be regulated by different epigenetic mechanisms, which also suggests that curcumin may act as a potential epigenetic modulator to influence tumor development [5].
Fig. 1 The molecular structure of curcumin.
Tumor immunotherapy is one of the most promising research directions in tumor treatment. Its therapeutic tools mainly include successive cell therapy, immunomodulatory therapy, tumor vaccine therapy, and targeted molecular therapy. In recent years, curcumin has been increasingly used in tumor immunotherapy. The anti-tumor effect is achieved by modulating the expression and activity of the bodyʼs intrinsic immune system, acquired immune system, and tumor-associated molecules in combination with immune checkpoint inhibitors and other tumor immunotherapy approach [6], [7], [8].
In this paper, we review the molecular mechanism of the antitumor effect of curcumin, the mechanism of immunomodulatory effect of curcumin, the reversal of tumor chemotherapy resistance, and the progress of research into a novel drug delivery system of curcumin based on the literature data of curcumin in tumor cells, animal models, and clinical trials, in order to provide new directions for the research of new antitumor drugs and clinical treatment of tumor with curcumin ([Fig. 1]).
Molecular Mechanism of Curcumin Against Tumors
Molecular Mechanism of Curcumin Against Tumors
Promotion of tumor cell apoptosis
Apoptosis is the autonomous and orderly death of cells under genetic control to maintain the stability of the internal environment. These three phenomena are prevalent in the biological world [9]. Curcumin promotes tumor cell apoptosis and can inhibit gastric cancer cell proliferation and induce apoptosis by activating the p53 signaling pathway through the upregulation of p53 and p21 [10], [11]. In addition, it also enhances the cell cycle blocking effect of paclitaxel on glioma cell C6, increases its cell proliferation inhibitory activity, increases the expression of pro-apoptotic proteins p53 and p21, activates caspase-3, and decreases the anti-apoptotic molecule Bcl-2, leading to apoptosis [12]. Curcumin inhibits the proliferation and promotes apoptosis of prostate cancer cells in vitro by inhibiting the activation of the intracellular segment (NICD)
through down-regulation of the expression of Notch1 and Jagged-1 genes in the Notch receptor family, which in turn affects the expression of its downstream target gene, Bcl-2, and promotes apoptosis [13]. By inhibiting the Wnt/β-catenin signaling pathway, it attenuates tumor cell viability, induces apoptosis, and significantly suppresses the levels of Wnt3a, LRP6, phosphorylated LRP6, β-catenin, phosphorylated β-catenin, C-myc, and survivin [14]. Inhibition of the PI3K signaling pathway by down-regulation of PI3K, phosphorylated protein kinase B (pAkt), and the phosphorylated rapamycin target protein (p-mTOR) inhibits proliferation and induces apoptosis in gastric cancer cell lines [10], [11]. Curcumin activates the p38 MAPK and JNK pathways and promotes apoptosis, as well as induces apoptosis by regulating MAPK/NF-κB, up-regulating
the p53/p21 pathway, down-regulating cyclin1 expression, and increasing the expression of Bax/caspase-3, leading to cell arrest in the G1 phase [15], [16]. Curcumin reduces cancer cell metastasis and invasion by inhibiting the activity of the JAK/STAT signaling pathway, inhibiting JAK/STAT3 phosphorylation and the expression of STAT3 downstream targets such as cell cycle protein B1, Bcl-xL, VEGF, and ICAM-1 [17]. Curcumin activates Bax protein expression and inhibits Bcl-2 protein expression to activate the Caspase-3 signaling pathway and promote tumor cell apoptosis [18], [19], [20]. Curcumin reduces the expression of MMP-2 and MMP-9 and the phosphorylation of ERK1/2, thereby inhibiting the metastasis and invasion of cancer cells [21]. Curcumin induces apoptosis by opening
the ATP-sensitive potassium pathway, leading to loss of mitochondrial membrane potential (MMP) [22]. Meanwhile, curcumin induces endoplasmic reticulum stress and mitochondrial dysfunction in human gastric cancer cells, initiating the Fas signaling apoptotic pathway [23], [24].
Induction of autophagy in tumor cells
Cellular autophagy is the directed transport of cytoplasmic substrates, macromolecules, and excess or damaged organelles to the lysosome for degradation in response to hypoxia, metabolic stress, and ATP depletion [25], [26]. Curcumin is able to regulate cellular autophagy by affecting the AMPK-mTOR signaling pathway. In response to a decrease in intracellular ATP or an increase in the AMP/ATP ratio, AMPK inhibits the activity of mTORC1, which in turn deregulates the inhibitory effect of mTORC1 on cellular autophagy [27], [28], [29]. Curcumin-treated lung adenocarcinoma A549 cells showed autophagosomes and autophagolysosomes, and the inhibition of autophagy increased the survival rate of A549 cells, suggesting that curcumin regulates the autophagic response associated with tumor survival [30]. And it can
upregulate the level of Beclin-1 protein (Beclin-1 is a key protein in the autophagy process, interacting with Bcl-2 family proteins to regulate the balance of autophagy and apoptosis) and autophagy-associated light-chain protein 3-II (LC3-II) to promote autophagy in human myeloid leukemia K562 cells [31]. Curcumin may affect the expression of autophagy-related genes by regulating the transcription factor TFEB, but the exact mechanism needs to be further investigated. Curcumin regulates autophagy and apoptosis by activating endoplasmic reticulum stress-regulated mitochondrial Ca2+ signaling; when curcumin acts on hepatocellular carcinoma Huh-7 cells, it activates endoplasmic reticulum stress signaling, leading to mitochondrial Ca2+ uptake, cytochrome c release, and initiation of apoptosis [32]. Curcumin decreased the expression of phosphorylated AKT, mTOR, and S6K1 when inducing autophagy in human melanoma A375 and
C8161 cells, as well as in gastric cancer SGC-7901 and BGC-823 cells, suggesting that curcumin inhibits the PI3K and AKT-mTORC1 signaling pathways and promotes cellular autophagy [10], [24]. Curcumin promotes vacuole formation and LC3-I to LC3-II conversion and induces autophagy in oral squamous tumor cells [33].
Inhibition of NF-κB activation
NF-κB controls a large number of tumor-related cell signaling pathways. Curcumin inhibits the expression of NF-κB [34]. NF-κB activates tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8, STAT3, cyclooxygenase-2 (COX-2), Bcl-2, matrix metalloproteinases, and vascular endothelial growth factor (VEGF), which in turn stimulate ROS, generate chronic inflammation, and lead to tumor growth [35]. Curcumin prevents the proliferation and invasion of cervical cancer HeLa cells by inhibiting the NF-κB and Wnt/β pathways [36] and also inhibits the proliferation, invasion, and metastasis of breast cancer cells by targeting the NF-κB signaling pathway [37]. Curcumin inhibits cancer cell proliferation and cell cycle protein D expression by down-regulating NF-κB expression, leading to cell cycle arrest in
G2/M and G2/S phases [33]. Further studies [38] showed that curcumin inhibited IκB-α (kappa B-α inhibitor) phosphorylation and promoted NF-κB degradation.
Inhibition of tumor angiogenesis and related growth factors
Tumor angiogenesis influences tumor growth and metastasis. Vascular endothelial growth factor (VEGF) promotes angiogenesis and tumor cell proliferation through an autocrine pathway that binds to endothelial cell surface receptors on blood vessels and lymphatic vessels and to tumor cell surface receptors. Signal transducer and activator of transcription 3 (STAT3) is highly expressed in tumors and is closely associated with tumor cell stage, depth of infiltration, lymph node metastasis and tumor grade [39]. Curcumin inhibits gastric cancer proliferation by down-regulating the DEC1-HIF-1a-STAT3-VEGF signaling pathway. Huang et al. [40] reported the important role of tumor mesenchymal stem cells (MSCs) in mediating tumor angiogenesis and found that curcumin inhibited the pro-angiogenic effects of GC-MSCs, possibly by inhibiting the NF-κB/VEGF signaling pathway, eliminating the role of cancer-derived MSCs in
driving tubule formation, migration, and colony formation in human umbilical vein endothelial cells (HUVEC). Other studies have shown that curcumin inhibits angiogenesis by down-regulating the expression of VEGF, angiopoietin-1 (Ang-1), Ang-2, PDGF, COX-2, hypoxia-inducible factor-1α (HIF-1α), transforming growth factor-β1 (TGF-β1), and basic fibroblast growth factor (bFGF). COX-2, hypoxia-inducible factor-1α (HIF-1α), transforming growth factor-β1 (TGF-β1), and basic fibroblast growth factor (bFGF) expression inhibits angiogenesis. It also inhibits angiogenesis through the inhibition of NF-κB, extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK), protein kinase C (PKC), pho-sphatidylinositol 3-kinase (PI3K), and matrix metalloproteinases [41]. Fan et al. [42] found that curcumin has a bi-directional regulatory effect in an
animal model of transplanted lung cancer combined with ischemia. Its mechanism of action may be through bidirectional regulation of the HIF-1α/mTOR/VEGF/VEGFR signaling pathway. Further proteomics studies confirmed that it reversed neutrophil elastase (NE)-induced angiogenesis in lung cancer tissues and could directly bind to NE or further inhibit NE by promoting the expression of α1- antitrypsin, suggesting that this compound may have a beneficial impact on the treatment of clinical ischemia combined with tumors.
High mobility group protein B1 (high-mobility group box-1, HMGB1) expression
High-mobility group protein B1 (HMGB1) is associated with vascular endothelial growth factor D (VEGF-D)-induced tumor lymphangiogenesis and tumor metastasis [43]. HMGB1 binds to different cell surface receptors such as Toll-like receptor 2 (TLR2), TLR4, and late glycosylation end product receptors to act on target cells and promote inflammation and tumor progression [44]. The effect of curcumin 50 µmol/L on the SGC-7901 cell line revealed that curcumin might inhibit lymphangiogenesis in gastric cancer by suppressing the HMGB1/VEGF-D signaling pathway [45]. The effect of curcumin on lymphatic vessel density in gastric cancer in vivo was observed by establishing a gastric cancer xenograft tumor model in nude mice, and curcumin was found to inhibit lymph node metastasis in gastric cancer [46]. AFRIN et al. [47] showed that curcumin
inhibited the progression of nonalcoholic steatohepatitis to hepatocellular carcinoma in mice by reducing the nuclear translocation of HMGB1 and NF-κB.
Inhibition of microtubule protein polymerization
Microtubules are polymers of α- and β-microtubule protein heterodimers, essential components of the eukaryotic cytoskeleton. Because interference with microtubule dynamics can stop the tumor cell cycle and induce apoptosis, microtubulin has become a preferred target for developing antitumor drugs [48], [49]. Studies with cervical cancer HeLa cells and breast cancer MCF-7 cells show that curcumin inhibits microtubule protein polymerization and promotes interphase and mitotic microtubule depolymerization [50]. Similarly, curcumin inhibits the dynamic instability of microtubules in breast cancer MCF-7 cells [51]. Therefore, curcumin can inhibit microtubule protein polymerization and act as an antitumor agent, which provides a new option for screening natural antitumor drugs and developing new drugs ([Fig. 2]).
Fig. 2 Molecular mechanism of Curcuminʼs antitumor activity. a Mechanism of curcumin-induced apoptosis in tumor cells. b Mechanism of curcumin inhibition of tumor cell proliferation.
Modulation of Tumor Immunity
Modulation of Tumor Immunity
Modulation of the intrinsic immune system
Intrinsic immune cells are the mainstay of the intrinsic immune response phase and include phagocytes such as macrophages, dendritic cells, and natural killer cells. Activated macrophages include both M1 and M2 phenotypes. M1-type macrophages, or classically activated macrophages, have antitumor effects, whereas M2-type macrophages, or selectively activated macrophages, promote tumor growth, metastasis, and invasion [52]. Curcumin can modulate the intrinsic immune system by promoting the conversion of macrophages to the M1 type, promoting the activation of natural killer cells and recruiting mature dendritic cells to clear tumors ([Fig. 3]). Studies have shown that curcumin treatment inhibits STAT3 and IL-10 expression, induces antitumor immune responses, attenuates inhibition of natural killer cell activity by tumor cells [53], [54], and promotes apoptosis of
tumor cells by enhancing recruitment of natural killer cells and cytotoxic T cells through specific combinations (e.g., TriCurin) [55]. In addition, curcumin can activate the immune system [56], upregulate TNF-α and IFN-γ expression, and effectively inhibit tumor growth and metastasis.
Fig. 3 Curcumin regulates the immune system.
Modulation of the acquired immune system
Regulation of the acquired immune system involves specific immune responses in which CD8+ T lymphocytes (cytotoxic T cells) and Th1 cells play a key role in antitumor immunity, whereas regulatory T cells (Treg) may inhibit antitumor immune responses [57]. Curcumin activates the acquired immune system against tumors and promotes the proliferation of central memory T cells and effector memory T cells through the following mechanisms: suppressing Treg cells and reducing their inhibitory effect on immune responses; enhancement of T cell proliferation and restoration of T cell numbers in the tumor host; induces a shift from Th2-type to Th1-type immune responses and attenuates tumor suppression of T cells; inhibits the expression of TGF-β and IL-10 and reduces Treg cell activity; reduces the suppression of tumor immune response by Treg cells by down-regulating CTLA-4 expression and regulating IL-2 levels [58], [59], [60].
Regulation of the expression and activity of tumor immune-related molecules
Tumors can promote T-cell apoptosis by secreting prostaglandin E2, and curcumin can inhibit this effect and prevent T-cell apoptosis induced by tumors ([Fig. 3]) [61]. Curcumin and basil polysaccharides down-regulate the expression of OPN, CD44, and MMP-9, with curcumin inhibiting CD44 more significantly [62] and inhibiting the expression and activity of IDO, reducing the suppression of T cell responses [63]. Meanwhile, curcumin inhibits CSN5 expression, decreases PD-L1 stability, and reduces tumor cell inhibition of specific CD8+ T cells [64].
Curcumin combined with immune checkpoint inhibitors for tumor treatment
Immune checkpoints (ICs) are a class of immunosuppressive molecules that regulate the bodyʼs immune strength. However, when ICs are over-expressed or over-functioning, the bodyʼs immunity is depressed, allowing tumors to grow and develop. Immune checkpoint inhibitors (ICIs) have recently been a hot topic in tumor immunotherapy. ICIs restore the pernicious effect of T cells on tumors by blocking immune checkpoints, thus blocking tumor immune escape [50]. The primary immune checkpoint inhibitors currently on the market are PD-1/PD-L1 inhibitors and IDO inhibitors, while curcumin can be used in combination with immune checkpoint inhibitors for oncology treatment.
CD8+ T cells express PD-1 upon activation, while tumor cells express PD-L1, and the combination of the two inhibits the anti-tumor function of CD8+ T cells. PD-1/PD-L1 antibodies, as one of the effective means of treating tumors, can block this inhibitory effect. Curcumin in combination with PD-1/PD-L1 inhibitors shows new potential in tumor therapy. Curcumin inhibits STAT3 activity, restores dendritic cell activity, enhances induction of tumor antigen-specific T cells, and shows synergistic antitumor activity with the PD-1/PD-L1 antibody in tumor models. A synergistic effect with anti-PD-1 slows down proliferation of hepatocellular carcinoma cells, activates lymphocytes, inhibits immune evasion, down-regulates TGF-β1 expression, and improves the tumor microenvironment [65]. In addition, the combination of curcumin and sildenafil enhances the efficacy of the PD-1 antibody and reduces the growth rate of gastrointestinal tumors. Curcumin
also inhibits NF-κB and STAT3 activities, enhances the function of tumor antigen-specific T-cells, and possesses significant synergistic antitumor activity with the PD-L1 antibody [66]. In addition to PD-1/PD-L1, IDO is also an immune checkpoint frequently used as a therapeutic target in tumor immunotherapy, which inhibits the proliferation and differentiation of immune cells, thus allowing tumors to evade the bodyʼs immune surveillance. Dai et al. [67] prepared the charge transfer delivery nanosystem PCPCD@NLG919, which is sensitive to acid-base and redox reactions, and loaded it with IDO inhibitor NLG919 and curcumin, which significantly promoted the proliferation of T cells, tumor-infiltrating B cells, and natural killer cells, as well as the maturation of dendritic cells in both in vitro and in vivo experiments, and efficiently induced apoptosis and inhibited tumor metastasis in
vitro.
Curcumin combined with other tumor immunotherapies for tumor treatment
The combination of curcumin and cell-peripheral immunotherapy showed synergistic antitumor effects. Chang et al. [68] found that curcumin could alter the tumor microenvironment, enhance the cytotoxicity of CD8+ T cells against tumors, up-regulate the number of CD8+ T cells, inhibit the expression of TGF-β and IDO in tumor cells, and effectively reduce the number of Treg cells. Tumor vaccines are a type of active immunotherapy, and the combination of curcumin and tumor vaccines shows therapeutic potential. Lu et al. [69] prepared a curcumin-polyethylene glycol conjugate (CUR-PEG) and Trp2 peptide vaccine combination for the treatment of melanoma and found that the combination significantly inhibited the expression of STAT3, IL-6, and CCL2, down-regulated the level of Treg cells, promoted M1 to M2 conversion, and increased CD8+ T cells. In melanoma treatment, the combination of curcumin and FAPα vaccine
exhibited synergistic antitumor effects, significantly inhibiting the growth of melanoma and prolonging the survival of mice [70]. Liu et al. [71] combined curcumin and nanovaccines in postoperative tumor therapy, effectively inducing immunogenic apoptosis of residual cancer cells, promoting CD8+ T lymphocyte infiltration within the tumor, significantly enhancing specific T-cell immunity and inhibition of local recurrence and metastasis of the tumor. In addition to PD-1/PD-L1, IDO is also a therapeutic target in tumor immunotherapy. Dai et al. [67] prepared a charge-transfer delivery nanosystem PCPCD@NLG919, which is sensitive to acid-base and redox reactions and loaded with the IDO inhibitors NLG919 and curcumin, which significantly promoted the T cells, tumor-infiltrating B-cells, and natural killer cell proliferation, as well as dendritic cell maturation, and efficiently induced tumor
cell apoptosis and inhibited tumor metastasis in vitro.
Reversal of Chemotherapy Resistance
Reversal of Chemotherapy Resistance
Chemotherapeutic resistance (chemoresistance) refers to the reduced sensitivity of cancer cells to chemotherapeutic drugs, resulting in resistance, and can be classified as congenital or acquired resistance or as prodrug resistance (PDR) and multidrug resistance (MDR) [72]. In a xenograft model, the combination of curcumin and 5-FU significantly inhibited tumor growth more than 5-FU alone, suggesting that curcumin reversed the drug-resistant effect of 5-FU, and the combination treatment increased the expression of miR-200C, confirming that curcumin treatment led to the up-regulation of miR-200C expression, which was associated with the inhibition of EMT (epithelial-mesenchymal transition) [73]. In the irinotecan-resistant colon cancer model, curcumin was able to reverse drug resistance by modulating the EMT pathway, up-regulating E-cadherin expression, and down-regulating waveform protein and N-cadherin expression [74]. Curcumin significantly inhibited the expression of CSC (cancer stem cell) recognition markers, reduced the characteristics of colonic CSCs, and induced apoptosis, reversing resistance to irinotecan [75].
Combination therapy with adriamycin (Dox-Cur) significantly reduces tumor cell survival, tumor ball formation, migration, and invasion, and the anticancer activity of the combination therapy is higher than that of the therapy alone [76]. Combination with chemotherapeutic agents reduces NF-κB activation, decreases Bcl-2 and Bcl-xL expression, enhances chemotherapy-induced apoptosis, and has a chemo-sensitizing effect [77]. Curcumin reversed multidrug resistance in the vincristine-resistant human gastric cancer cell line SGC-7901/VCR, which may be related to reducing the function and expression of P-glycoprotein (P-gp) and promoting the activation of Caspase-3 [78]. Curcumin enhanced the pro-apoptotic effect of cisplatin on SGC-7901 cells, possibly by inhibiting the expression of the p-Akt gene and Bcl-2 protein, while upregulating the expression of T-Akt and p53 genes [77].
Epigenetic Mechanism of Curcumin Antitumor Effect
Epigenetic Mechanism of Curcumin Antitumor Effect
Altered DNA methylation status
DNA methylation is an epigenetic modification in the mammalian genome that is closely associated with gene expression regulation, transposon repression, aging, and cancer development [79], [80], [81]. It usually occurs in CpG islands, especially in 70% of the CpG dinucleotides in mammals [82]. DNA methylation has been associated with transcriptional silencing, and in particular, the methylation status of promoter CpG islands is negatively correlated with the level of gene expression, i.e., hypermethylation leads to transcriptional silencing, whereas hypomethylation promotes gene transcription. In addition, methylation of gene bodies is not associated with transcriptional repression and may be due to selective activation and selective shearing of promoters within genes. Altered genomic methylation is one of the main features of cancer cells and is usually
associated with overexpression of DNA methylation and demethylation enzymes.
Curcumin, as a DNA methylation transferase inhibitor, can regulate the expression of related genes by (i) modulating the activity of related enzymes during the maintenance of DNA methylation and (ii) regulating the expression of DNA methylation enzymes. Curcumin can directly bind to DNA methyltransferase 1 (DNMT1) and covalently block the sulfur-catalyzing effect of DNMT1, thus inhibiting the activity of DNMT1 and significantly reducing the protein expression level of DNMT1 in breast cancer cells [20]. In addition, curcumin promotes p21 expression through mitochondrial oxidative damage, and the upregulation of p21 further inhibits DNMT1 expression through the p53-p21/GADD45A-cyclin/CDK-Rb/E2F-DNMT1 axis, which promotes genomic DNA demethylation and induces apoptosis in gastric cancer cells [83]. Curcumin also enhances p21 expression by decreasing the methylation level of the p21 promoter and may simultaneously promote
p21 expression during tumor suppression through multiple mechanisms [84] with a feedback mechanism ([Fig. 4]). In ovarian cancer cell lines, curcumin regulates the DNA methylation status of genes by decreasing the expression of DNA methyltransferase 3A (DNMT3A) [85]. The inhibitory effect of curcumin on gastric cancer is mainly through direct binding to TETs via hydrogen bonding, which promotes the reactivation of TETs and thus increases the methylation level of the RB1 promoter [86]. [Table 1] summarizes the effects of curcumin on the methylation status of various tumors [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100].
Fig. 4 Curcumin promotes apoptosis of cancer cells through DNA methylation.
Table 1 Genes with altered methylation status by curcumin in tumors.
|
Type of Cancer
|
Genes
|
Mechanism of Action
|
References
|
|
Prostate Cancer
|
AR
|
AR promoter methylation level ↓; AR expression ↑
|
[87]
|
|
NRF2
|
NRF2 promoter region − 1266 to − 1086 bp dimethylation level ↓; NRF2 expression ↑
|
[88]
|
|
NEUROG1
|
NEUROG1 promoter methylation level ↓; NEUROG1 expression ↑
|
[89]
|
|
CDX2
|
DNMT1 and DNMT3A ↓; CDX2 promoter methylation level ↓; CDX2 expression ↑
|
[90]
|
|
Colorectal Cancer
|
DLEC1
|
↓ expression of DNMT1 and TET1; ↑ expression of DNMT3A and DNMT3B.
|
[91]
|
|
TNF
|
DNMT1 expression ↓ by downregulating transcription factor SP1; DLC1 promoter methylation level ↓; DLC1 expression ↑
|
[92]
|
|
BRCA1
|
GSTP1 promoter methylation level ↓; GSTP1 expression ↑
|
[93]
|
|
SNCG
|
DNMT1 ↓; RASSF1A promoter methylation level ↓; RASSF1A expression ↑
|
[94]
|
|
Lung Cancer
|
RARβ
|
Methylation status ↓; WIF-1 expression ↑
|
[95]
|
|
WIF-1
|
RARβ promoter methylation level ↓; RARβ expression ↑
|
[96]
|
|
Gastric Cancer
|
RB1
|
Curcumin binds to TET2 and TET3 via hydrogen bonding, reactivating TETs and increasing RB1 promoter methylation levels ↓; RB1 expression ↑
|
[97]
|
|
Nephroblastoma
|
RECK
|
RECK promoter methylation level ↓; RECK expression ↑; resulting in MMP2 and MMP9 expression ↓
|
[98]
|
|
Ovarian Cancer
|
SFRP5
|
Reducing the expression of DNMT3A by inhibiting the activity of DNMTs leads to ↓ of SFRP5 methylation level and promotes the expression of SFRP5
|
[99]
|
|
Glioblastoma
|
RANK
|
NF-κB promoter methylation level ↓; NF-κB expression ↑
|
[100]
|
Affecting histone modifications
Histone-mediated post-translational modification (PTM) is an important chromatin modification mechanism that regulates gene expression, including acetylation, methylation, phosphorylation, and many other ways [101], [102], [103]. Abnormal histone modifications may lead to tumor or cancer development. Curcumin, as a natural compound, is able to regulate histone modification and thus inhibit tumor development through the following mechanisms: ability to induce acetylation and glutathionylation of histone H3, which inhibits the viability and proliferation of cancer cells [103], [104], [105], [106]; ability to silence EZH2 (Drosophila zeste gene human homolog of enhancer 2), restore expression of DLC1 (hepatocellular carcinoma deletion gene 1), and inhibit migration, invasion,
and proliferation of triple-negative breast cancer cells [107]. It was able to reduce the mRNA level and protein concentration of PRMT5 (arginine methyltransferase 5) and inhibit cancer cell proliferation [108].
Influence on Non-Coding RNA Expression
Influence on Non-Coding RNA Expression
miRNA
MicroRNAs (miRNAs) are a class of endogenous small ribonucleic acids about 20 – 24 nucleotides in length, which play a variety of important regulatory roles in cells. miRNAs regulate the expression of multiple genes through a complex regulatory network, either a single miRNA, or multiple miRNAs finely regulate the expression of a single gene [109], [110]. Many miRNAs function as oncogenes or tumor suppressors, and the dysregulation of their expression is closely related to the occurrence, development, and metastasis of cancer [111], [112].
Curcumin is able to regulate multiple molecular targets and signal transduction pathways by affecting miRNA expression, thereby inhibiting tumor progression. Specifically, curcumin can regulate the expression of proto-oncogenes (e.g., miR-19a and miR19b), as well as oncogenic miRNAs (e.g., miR-15a, miR-16, miR-34a, miR146b 5 p, and miR-181b) in breast cancer cells [113]. In addition, curcumin was able to influence tumor growth, invasion, and metastasis by inhibiting the transcription of miR-21 and stabilizing the expression of the colorectal cancer oncogene PDCD4 [114]. Curcumin also alters the distribution of miR-21 in the cytoplasm and exosomes of chronic granulocytic leukemia cells, decreasing miR-21 levels in the cytoplasm and promoting the expression of the target gene PTEN; elevated levels of miR-21 in the exosomes inhibit the expression of MARCKS, which collectively leads to the down-regulation of VEGF
expression and maintenance of vascular integrity ([Fig. 5 a]) [115], [116]. Curcumin can also alter the DNA methylation status and affect gene expression, a mechanism also present in the regulation of miRNA expression. Studies have shown that curcumin can alter the methylation status of miRNA promoters in bladder cancer, promoting the expression of miR-203, which in turn inhibits the expression of downstream target genes ([Fig. 5 b]) [117]. Among the miRNAs affected by curcumin, such as miR-130a, miR-34a and miR-9 promoters are regulated by DNA methylation [118], [119], which implies that curcumin can participate in the expression of other miRNAs through the mechanism of DNA methylation to exert anti-cancer effects. The radiosensitizing effect of curcumin on tumor cells
also relies on the regulation of miRNA expression, mainly including miR-186, miR-30c, miR-146a, miR-200c, miR-143, miR-145, miR-1246, and miR-124 [120], [121], [122], [123], [124], [125], [126]. Specifically, curcumin improved tumor sensitivity to chemotherapeutic agents by up-regulating the expression of miR-200c and targeted PRC, achieving chemosensitization to colorectal cancer [140]. This result links miRNAs to histone modifications, suggesting that curcumin is involved in the regulation of complex epigenetic mechanisms in exerting its anticancer effects. We summarize the reported miRNAs regulated by curcumin in [Table 2]
[114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153].
Fig. 5 Curcumin inhibits cancer cell growth via miRNA.
Table 2 Curcumin-regulated miRNAs in cancer.
|
Type of Cancer
|
miRNA
|
Mechanism of Action
|
References
|
|
Notes: ↓: Lower Expression; ↑: High Expression
|
|
Nasopharyngeal Carcinoma
|
miR-125a-5p
|
miR-125a-5p expression ↑, TP53 expression ↓
|
[127]
|
|
miR-7
|
miR-7 expression ↑, SKP2 expression ↓, which in turn promotes p21 expression
|
[128]
|
|
Multiple myeloma
|
miR-101
|
miR-101 expression is ↑, EZH2 expression is ↓, and there is feedback regulation
|
[129]
|
|
miR-206
|
miR-206 expression ↑, inhibits PI3K/AKT/mTOR pathway
|
[130]
|
|
Multiple myeloma
Lung Cancer
|
miR-192 – 5 p
|
miR-192 – 5 p expression ↑, c-MYC expression ↓, and inhibition of Wnt/β-catenin signaling pathway
|
[131]
|
|
miRNA-548ah-5p
|
miRNA-548ah-5p expression ↑, may promote apoptosis of cancer cells through cell cycle proteins, and by gene set variation variant analysis (GSVA) whose target genes may be CCNF, LOX1, MRGPRF and VEGF
|
[132]
|
|
miR-98
|
miR-98 expression ↑, LIN28A, MMP2 and MMP9 expression ↓
|
[133]
|
|
miR-330 – 5 p
|
miR-330 – 5 p expression↑
|
[134]
|
|
miR-192 – 5 p,miR-215
|
Curcumin promotes miR-192 – 5 p, miR-215 expression ↑ through P53 and P21 expression, which in turn leads to XIAP ↓
|
[135]
|
|
Lung Cancer
|
miR-186
|
miR-186 expression was ↓, CASPASE-10 expression was ↑, while miR-186 expression was ↓ to achieve chemosensitization
|
[121], [135]
|
|
miR-30c
|
miR-30c expression ↑, MTA1 expression ↓, chemosensitizing effect achieved
|
[121], [122]
|
|
miR-192 – 5 p
|
miR-192 – 5 p expression ↑, inhibits PI3K/Akt signaling pathway
|
[136]
|
|
miR-21
|
miR-21 expression ↓, PTEN expression ↑
|
[137]
|
|
Liver Cancer
|
miR-21 – 5 p
|
miR-21 – 5 p expression ↓, SOX6 expression ↑
|
[138]
|
|
miR-19A
|
miR-19A expression ↑, CTGF expression ↓
|
[139]
|
|
Colorectal Cancer
|
miR-200c
|
Upregulation of miR-200c, which inhibits PRC (multiple comb inhibitory complex), leads to histone H3K27me3 and achieves chemosensitization
|
[140]
|
|
miR-34a and miR-27a
|
miR-34a and miR-27a expression ↑
|
[141]
|
|
miR-21
|
Blocked AP-1 binding to miR-21 promoter, resulting in ↓ miR-21 expression and promoting PDCD4 expression ↑
|
[114]
|
|
Prostate Cancer
|
miR-770 – 5 p and miR1247
|
Inhibition of prostate cancer cell growth by regulating the expression of specific miRNAs (miR-770 – 5 p and miR1247) in the DLK1-DIO3 imprinted gene cluster
|
[142]
|
|
miR-143/miR-145 cluster
|
Induces autophagy by suppressing miRNA promoter methylation levels, leading to ↑ miR-143/miR-145 expression and achieve radiosensitization of prostate cancer
|
[124]
|
|
Breast Cancer
|
miR-142 – 3 p
|
Inhibition via p300/miR-142 – 3 p/PSMB5 axis and consequently 20S proteasome
|
[143]
|
|
miR-34a
|
miR-34a expression ↑, AXL, SLUG, CD24, RHO-A expression ↓
|
[144]
|
|
miR-34a
|
miR-15a and miR-16 expression ↑, BCL2 expression ↓
|
[145]
|
|
Pancreatic Cancer
|
miR-22
|
miRNA-22 expression ↑, SP1 and ESR1 expression ↓
|
[146]
|
|
miR-7
|
miR-7 expression ↑, SET8 and LIF2 expression ↓
|
[147]
|
|
Ovarian Cancer
|
miR-9
|
miR-9 expression ↑, decreased AKT and FOXO1 phosphorylation
|
[148]
|
|
miR-214
|
miR-214 expression ↓ for chemosensitization
|
[126]
|
|
Renal cell carcinoma
|
miR-106b-5p
|
miR-106b-5p expression ↓, p21 expression ↑
|
[149]
|
|
Esophageal Cancer
|
miR-21, miR-34a and let-7a
|
miR-21, miR-34a expression ↓, let-7a expression ↑
|
[150]
|
|
Gastric Cancer
|
miR-34a
|
miR-34a expression ↑, BCL2, CDK4 and cyclin D1 expression ↓
|
[151]
|
|
miR-21
|
miR-21 expression ↓, PTEN expression ↑, and inhibition of AKT phosphorylation
|
[152]
|
|
miR-33b
|
miR-33b expression ↑, XIAP expression ↓
|
[153]
|
lnc-RNA
Long non-coding RNAs (lncRNAs) are a class of non-coding RNA molecules that play important roles in the nucleus or cytoplasm of cells, and they can regulate gene expression by binding to epigenetic proteins or as ceRNAs that competitively bind to microRNAs [154]. In a variety of tumors, aberrant expression of lncRNAs is closely associated with tumorigenesis, progression, and metastasis, with some lncRNAs promoting tumor progression while others suppress it [155], [156]. For example, LncRNA CASC9 is aberrantly expressed in a variety of malignant tumors, and its overexpression accelerates cell proliferation, invasion, and migration, enhances drug resistance of tumor cells, and inhibits apoptosis, similar to the role of oncogenes [157].
Curcumin exerts its inhibitory effect on lncRNAs in two ways: (i) regulating miRNAs through the ceRNA effect of lncRNAs and (ii) directly inhibiting the expression of tumor-associated lncRNAs (e.g., H19 and LncRNA-PVT1). It was shown that curcumin inhibited the expression of lncRNA-ROR while up-regulating miR-145 in human prostate cancer stem cells and inhibited the proliferation and in vitro invasion of human prostate cancer stem cells through the ceRNA effect of lncRNA-ROR and miR145 [46], and it was also shown that lncRNA-ROR could target binding to miR-185- 3 p, miR-26, and miR-206 and affect the growth of cancer cells [158], [159], [160]. Of course, in addition to exerting ceRNA effects, lncRNA-ROR appears to influence tumor development through other pathways, such as, for example, by inhibiting the growth of hepatocellular carcinoma cells
through inactivation of the WNT pathway [161] and acting as a decoy molecule to recruit MLL1 methylation transferase, promote histone methylation of the TIMP3 gene H3K4, and induce breast cancer [152], and is significantly associated with multi-drug resistance in tumor cells [162] ([Fig. 6]). In addition, long-term radiotherapy and chemotherapy can lead to the tolerance of cancer cells. At the same time, curcumin can enhance or reverse cancer cellsʼ sensitivity to radiotherapy and chemotherapy by regulating the expression of lncRNA. Yoshida et al. used curcumin to inhibit the expression of EZH2 and lncRNA-PVT1 from reactivating the chemical sensitivity of drug-resistant cancer cells. This effect came from two aspects: (i) lncRNA-PVT1 can act as a protein complex scaffold to bind to PRC and affect histone modifications, and curcumin inhibited the expression of
lncRNA-PVT1 to reduce PRC complex formation; (ii) EZH2 is an essential component of PRC subunits, and curcumin similarly reduced the protein level of EZH2 [163]. Another study showed that curcumin could up-regulate miR-101 and inhibit the translation of EZH2 through 3′UTR targeting [129]. Interestingly, other studies have confirmed that lncRNA-PVT1 can affect EZH2 expression by binding miRNA-526b [164]. There have been many reports on the cancer-inhibiting effects of curcumin, but studies involving the regulation of circRNA to inhibit the proliferation and migration of cancer cells are still rare. A recent study analyzed poor circRNA in radioresistant nasopharyngeal carcinoma cell lines treated with curcumin using high-volume circRNA microarray technology and showed that curcumin inhibits epidermal growth factor receptor (EGFR), transcriptional activator 3 (STAT3), and growth factor
receptor binding protein 2 (GRB2) through a circRNA/miRNA/mRNA regulatory network (GRB2) to achieve radiosensitization of cancer cells [165], [166]. It has also been shown that curcumin can regulate non-small cell lung carcinogenesis by inhibiting the expression of circ-PRKCA, and this mechanism is dependent on the adsorption of circ-PRKCA on miR-384 [166]. We summarize the reported lncRNAs regulated by curcumin in [Table 3]
[161], [162], [163], [164], [165], [166], [167], [168], [169], [170], [171], [172], [173], [174], [175], [176], [177].
Fig. 6 Curcumin inhibits cancer cell growth via lncRNA-ROR.
Table 3 Curcumin-regulated lncRNAs in cancer.
|
Type of Cancer
|
LncRNA
|
Mechanism of Action
|
References
|
|
Notes: ↓: Lower Expression; ↑: High Expression
|
|
Colorectal Cancer
|
LncRNA-NBR2
|
LncRNA-NBR2 expression ↑ through AMPK pathway inhibits cancer cell growth
|
[167]
|
|
LncRNA-KCNQ1OT1
|
LncRNA-KCNQ1OT1 expression ↓, attenuating the ceRNA of LncRNA-KCNQ1OT1 on miR-497 effect, resulting in ↓ expression of BCL2 and achieving chemosensitization effect
|
[163]
|
|
Breast Cancer
|
H19
|
H19 expression ↓, inhibiting H19-induced cancer cell migration and invasion, achieving chemosensitization
|
[168]
|
|
Prostate Cancer
|
LncRNA-ROR
|
The ceRNA effect of cRNA-ROR on miR-145 leads to low expression of OCT4
|
[169]
|
|
Stomach Cancer
|
H19
|
Promoting p53 activation through c-MYC leading to H19 expression low expression
|
[170]
|
|
Lung Cancer
|
LncRNA-UCA1
|
LncRNA-UCA1 expression ↓, inhibits WNT and mTOR pathway
|
[171]
|
|
lncRNA-MEG3
|
lncRNA-MEG3 expression ↑, promoting PTEN expression, achieving chemosensitization
|
[172]
|
|
Liver Cancer
|
LncRNA-ROR
|
LncRNA-ROR expression ↓, inhibition of Wnt/β-catenin pathway pathway
|
[161]
|
|
Glioma Glioma
|
H19
|
H19 and miR-675 expression ↓, regulated by negative feedback inhibition of glioma growth
|
[173]
|
|
Nasopharyngeal Carcinoma
|
LncRNA-AK294 004
|
This LncRNA can lower the expression of CCND1 gene through its 3′UTR to reduce its expression, and curcumin can lead to ↓ expression of LncRNAAK294004, promote CCND1 expression, and realize the sensitizing effect of radiotherapy
|
[174]
|
|
Renal cell Cancer
|
lncRNA-HOTAIR
|
lncRNA-HOTAIR expression ↓, inhibiting cancer cell migration migration
|
[170]
|
Novel Drug Delivery System for Curcumin
Novel Drug Delivery System for Curcumin
Researchers are developing a variety of novel delivery systems to enhance the antitumor efficacy and bioavailability of curcumin without increasing toxicity. Nanoparticles serve as carriers for continuous drug delivery and protect the active ingredient during transport, altering tissue distribution and drug clearance. They can be used for multiple routes of administration, such as oral, nasal, and intravenous, and can enhance drug bioavailability. For example, in a study by Kanai et al. [171], plasma levels of curcumin were significantly increased in healthy volunteers after oral administration of curcumin nanoparticles, indicating enhanced bioavailability. The curcumin nanoparticle formulations prepared by Bahare [172] were superior to curcumin in terms of activity, targeting selectivity, and bioavailability. Liposomes, consisting of a phospholipid bilayer shell and an aqueous core, are ideal carriers for
encapsulating hydrophobic and hydrophilic compounds. Despite the low encapsulation rate (45%), curcumin liposomes showed 20-fold higher cytotoxicity than curcumin in a variety of cell lines. Different types of curcumin-loaded long-circulating liposomes prepared by Mahmud et al. [173] showed strong anticancer activity against human pancreatic adenocarcinoma AsPC-1 and BxPC-3 cells but were weakly toxic to normal cell lines. Biodegradable synthetic polymers (e.g., poly(lactide-co-glycolide) [PLGA]) and natural polymers (e.g., serine proteins and chitosan) have been widely used for drug delivery. Studies have shown that PLGA-curcumin is at least 15-fold more effective than natural curcumin in preventing blood–brain barrier disruption and inhibiting inflammatory cytokines [174]. Solid dispersion drug delivery has emerged as an efficient mode of delivery for administering efficacious but poorly water-soluble anticancer
drugs. A rat study [179] found that the gastric bioavailability of curcumin from micellar solid dispersions was 19 times higher than that of free curcumin. Micelles are aqueous formulations that improve hydrophobic drugs, prolong drug circulation time in the body, increase cellular uptake, and target tumor regions. Zhang et al. [180] prepared novel nanomicelles (PPNMs) with up to a 96.7% encapsulation rate, which can control the release of curcumin precursor drugs through redox reactions.
Summary and Perspective
As a natural compound, curcumin can combat tumor development through a variety of mechanisms, including promoting apoptosis, modulating cellular autophagy, and influencing the NF-κB signaling pathway, and these mechanisms of action provide a deeper understanding of Curcuminʼs antitumor activity. It has also been shown to alter epigenetic mechanisms [181], which may lead to increased sensitivity of cancer cells to conventional drugs, thereby inhibiting tumor growth. This mechanism provides a new perspective on curcumin as a potential anticancer therapeutic agent. The combination of curcumin with other treatments such as PD-1/PD-L1 inhibitors shows novel therapeutic potential, which may provide new strategies for tumor treatment.
Although the antitumor effects of curcumin have been widely verified in in vitro experiments, its effects in vivo may be affected by a variety of factors, including bioavailability, metabolic stability, and the dose-effect relationship. Therefore, although curcumin showed antitumor activity in in vitro experiments, its in vivo effect and clinical application value still need to be verified by more in vivo studies and clinical trials. The antitumor potential of curcumin is worthy of further investigation, but its nature as a PAIN or IMP needs to be evaluated through rigorous scientific studies. PAINs may interfere with experimental readings by reacting with reagents, enzymes, or other proteins used in the experiments or by affecting intracellular signaling pathways. IMPs may interfere with experimental readings because they are unable to efficiently cross the cellular membrane and are in vivo because of their inability to cross cell
membranes efficiently, because they are rapidly metabolized or excreted or because they are not present in the body in sufficient concentrations to produce a therapeutic effect. The identification and exclusion of PAINs and IMPs are important in drug research because they help to ensure the reliability of the results and the efficacy of the drug candidate. Researchers need to exclude these interfering factors through rigorous experimental design, controlled experiments, and validation experiments to ensure that the activity of the drug candidate is real and effective. Also, the multi-targeted mechanism of action of curcumin may lead to non-specific biological effects, which need to be attended to and controlled in research. Adverse effects of curcumin such as gastrointestinal reactions, contact dermatitis, hepatobiliary toxicity, and immunologic adverse events have also been reported in the literature [182].
In conclusion, curcumin, a traditional Chinese medicine extract, acts as an anticancer agent, chemosensitizer, and immunomodulator through various complex mechanisms. Compared with traditional chemotherapeutic agents, chemo-sensitizers, and immune checkpoint inhibitors, curcumin is widely available, inexpensive, and safe. It can be widely used as an antitumor prophylactic agent. However, its bioavailability is a key limiting factor for its use as a therapeutic agent and still requires further research; therefore, the development of curcumin derivatives or novel nanoformulations is crucial for improving the bioavailability of curcumin and enhancing its anticancer effects [183].
Search Strategy
-
Databases: PubMed, Web of Science, Embase, and Google Scholar English databases.
-
Search terms: curcumin was used as the core search term, and antitumor molecular mechanism, tumor immunity, epigenetics, drug delivery, drug delivery system were used as the related subject terms for the search.
-
Search method: use Boolean operators (AND, OR) to combine search terms, “curcumin AND (antitumor molecular mechanism OR epigenetics OR tumor immunity OR drug delivery OR drug delivery system)”.
In PubMed, a precise search was performed using the MeSH vocabulary, using the MeSH term “Curcumin” in conjunction with the relevant subject terms described above.
In Web of Science, the search was performed using subject terms and related subject headings, and the citation index was used to track related literature.
In Embase, subject searches were conducted using the Emtree vocabulary and free words were used to extend the search.
In Google Scholar, full-text searches were performed directly using combinations of search terms.
-
Search date: 2014.1.1 – 2024.6.30
-
Criteria for exclusion: exclude literature of lower quality and articles or preprints that have not been peer-reviewed. Exclude non-English literature.
Contributorsʼ Statement
Xin Wan designed the structure of the article and finished writing the paper as the first author. Dong Wangacted as corresponding author rearching the database and extracting literature, drawing the figures, all authors declare no conflict of interest.
