Fisetin's Promising Antitumor Effects: Uncovering Mechanisms and Targeting for Future Therapies

Abstract

Background Cancer remains a critical global health challenge and a leading cause of mortality. Flavonoids found in fruits and vegetables have gained attention for their potential anti-cancer properties. Fisetin, abundantly present in strawberries, apples, onions, and other plant sources, has emerged as a promising candidate for cancer prevention. Epidemiological studies linking a diet rich in these foods to lower cancer risk have sparked extensive research on fisetin’s efficacy.

Objective This review aims to comprehensively explore the molecular mechanisms of fisetin's anticancer properties and investigate its potential synergistic effects with other anticancer drugs. Furthermore, the review examines the therapeutic and preventive effects of fisetin against various cancers.

Methods A systematic analysis of the available scientific literature was conducted, including research articles, clinical trials, and review papers related to fisetin’s anticancer properties. Reputable databases were searched, and selected studies were critically evaluated to extract essential information on fisetin’s mechanisms of action and its interactions with other anticancer drugs.

Results Preclinical trials have demonstrated that fisetin inhibits cancer cell growth through mechanisms such as cell cycle alteration, induction of apoptosis, and activation of the autophagy signaling pathway. Additionally, fisetin reduces reactive oxygen species levels, contributing to its overall anticancer potential. Investigation of its synergistic effects with other anticancer drugs suggests potential for combination therapies.

Conclusion Fisetin, a bioactive flavonoid abundant in fruits and vegetables, exhibits promising anticancer properties through multiple mechanisms of action. Preclinical trials provide a foundation for further exploration in human clinical trials. Understanding fisetin’s molecular mechanisms is vital for developing novel, safe, and effective cancer prevention and treatment strategies. The potential synergy with other anticancer drugs opens new avenues for combination therapies, enhancing cancer management approaches and global health outcomes.

Keywords

apoptosis - autophagy - cell cycle arrest - fisetin

Author Contributions

All named authors take responsibility for the integrity of the work as a whole and have given final approval for the version to be submitted. E.Q., B.Al-H., A.Al-M., and A.Q. were responsible for writing and designing the study. H.A. and J.C.M. were responsible for designing and implementing the idea, collection of results, and writing the manuscript and drawing the figures. M.A. and M.Al-N. were responsible for writing and designing the study. J.A. and E.A. were responsible for writing and revising the manuscript. M.S., Z.G., Z.T., and X.M. were responsible for the manuscript. All authors reviewed the manuscript.

Ethical Approval

This is a review article and ethical approval is not applicable.

Data Availability

Not applicable.

^# Equal contributions.

Publikationsverlauf

Artikel online veröffentlicht:
09. August 2023

• References

• 1 Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65 (02) 87-108
• 2 Singh SR. Cancer stem cells: recent developments and future prospects. Cancer Lett 2013; 338 (01) 1-2 [Internet]
• 3 Kasala ER, Bodduluru LN, Madana RM, v AK, Gogoi R, Barua CC. Chemopreventive and therapeutic potential of chrysin in cancer: mechanistic perspectives. Toxicol Lett 2015; 233 (02) 214-225 [Internet]
• 4 Teiten MH, Eifes S, Dicato M, Diederich M. Curcumin-the paradigm of a multi-target natural compound with applications in cancer prevention and treatment. Toxins (Basel) 2010; 2 (01) 128-162
• 5 Cragg GM, Pezzuto JM. Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Med Princ Pract 2016; 25 (Suppl 2, Suppl 2): 41-59
• 6 Muhammad N, Usmani D, Tarique M. et al. The role of natural products and their multitargeted approach to treat solid cancer. Cells 2022; 11 (14) 2209
• 7 Russo M, Spagnuolo C, Tedesco I, Russo GL. Phytochemicals in cancer prevention and therapy: truth or dare?. Toxins (Basel) 2010; 2 (04) 517-551
• 8 Arai Y, Watanabe S, Kimira M, Shimoi K, Mochizuki R, Kinae N. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr 2000; 130 (09) 2243-2250
• 9 Ul Islam B, Suhail M, Khan MS. et al. Flavonoids and PI3K/Akt/mTOR signaling cascade: a potential crosstalk in anticancer treatment. Curr Med Chem 2021; 28 (39) 8083-8097
• 10 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
• 11 Pal HC, Sharma S, Elmets CA, Athar M, Afaq F. Fisetin inhibits growth, induces G₂ /M arrest and apoptosis of human epidermoid carcinoma A431 cells: role of mitochondrial membrane potential disruption and consequent caspases activation. Exp Dermatol 2013; 22 (07) 470-475
• 12 Tabrez S, Hoque M, Suhail M. et al. Identification of anticancer bioactive compounds derived from Ficus sp. by targeting Poly [ ADP-ribose ] polymerase 1 (PARP-1) Journal of King Saud University – Science Identification of anticancer bioactive compounds derived from Ficus sp. by targeting Poly [ ADP-ribose ] polymerase 1 (PARP-1). J King Saud Univ Sci 2022; 34: 102079 [Internet]
• 13 Abuzenadah AM, Al-Sayes F, Mahafujul Alam SS. et al. Identification of potential poly (ADP-Ribose) polymerase-1 inhibitors derived from Rauwolfia serpentina: possible implication in cancer therapy. Evid Based Complement Alternat Med 2022; 2022: 3787162
• 14 Lim DY, Park JHY. Induction of p53 contributes to apoptosis of HCT-116 human colon cancer cells induced by the dietary compound fisetin. Am J Physiol Gastrointest Liver Physiol 2009; 296 (05) G1060-G1068
• 15 Kashyap D, Sharma A, Sak K, Tuli HS, Buttar HS, Bishayee A. Fisetin: a bioactive phytochemical with potential for cancer prevention and pharmacotherapy. Life Sci 2018; 194: 75-87 [Internet]
• 16 Imran M, Saeed F, Gilani SA. et al. Fisetin: an anticancer perspective. Food Sci Nutr 2020; 9 (01) 3-16
• 17 He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43: 67-93
• 18 Sundarraj K, Raghunath A, Panneerselvam L, Perumal E. Fisetin inhibits autophagy in HepG2 Cells via PI3K/Akt/mTOR and AMPK pathway. Nutr Cancer 2021; 73 (11-12): 2502-2514 [Internet]
• 19 Haddad AQ, Fleshner N, Nelson C. et al. Antiproliferative mechanisms of the flavonoids 2,2′-dihydroxychalcone and fisetin in human prostate cancer cells. Nutr Cancer 2010; 62 (05) 668-681
• 20 Khan N, Afaq F, Syed DN, Mukhtar H. Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells. Carcinogenesis 2008; 29 (05) 1049-1056
• 21 Syed DN, Afaq F, Maddodi N. et al. Inhibition of human melanoma cell growth by the dietary flavonoid fisetin is associated with disruption of Wnt/β-catenin signaling and decreased Mitf levels. J Invest Dermatol 2011; 131 (06) 1291-1299 [Internet]
• 22 Khan MS, Husain FM, Rehman MT. et al; Badar Ul Islam. mTOR targeted cancer chemoprevention by flavonoids. Curr Med Chem 2021; 28 (39) 8068-8082
• 23 Syed DN, Chamcheu JC, Khan MI. et al. Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. Biochem Pharmacol 2014; 89 (03) 349-360 [Internet]
• 24 Dickson MA, Schwartz GK. Development of cell-cycle inhibitors for cancer therapy. Curr Oncol 2009; 16 (02) 36-43
• 25 Haddad AQ, Venkateswaran V, Viswanathan L, Teahan SJ, Fleshner NE, Klotz LH. Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis 2006; 9 (01) 68-76
• 26 Lu X, Jung Ji, Cho HJ. et al. Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. J Nutr 2005; 135 (12) 2884-2890
• 27 Chien CS, Shen KH, Huang JS, Ko SC, Shih YW. Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol Cell Biochem 2010; 333 (1-2): 169-180
• 28 Liao YC, Shih YW, Chao CH, Lee XY, Chiang TA. Involvement of the ERK signaling pathway in fisetin reduces invasion and migration in the human lung cancer cell line A549. J Agric Food Chem 2009; 57 (19) 8933-8941
• 29 Chen CM, Hsieh YH, Hwang JM. et al. Fisetin suppresses ADAM9 expression and inhibits invasion of glioma cancer cells through increased phosphorylation of ERK1/2. Tumour Biol 2015; 36 (05) 3407-3415
• 30 Chou RH, Hsieh SC, Yu YL. et al. Fisetin Inhibits migration and invasion of human cervical cancer cells by down-regulating urokinase plasminogen activator expression through suppressing the p38 MAPK-dependent NF-κB signaling pathway. PLoS One 2013; 8: 1-12
• 31 Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science 2011; 331 (6024) 1559-1564
• 32 Li R, Zhao Y, Chen J, Shao S, Zhang X. Fisetin inhibits migration, invasion and epithelial-mesenchymal transition of LMP1-positive nasopharyngeal carcinoma cells. Mol Med Rep 2014; 9 (02) 413-418
• 33 Khan MI, Adhami VM, Lall RK. et al. YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin. Oncotarget 2014; 5 (09) 2462-2474
• 34 Pal HC, Diamond AC, Strickland LR. et al. Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma. Oncotarget 2016; 7 (02) 1227-1241
• 35 Kang KA, Piao MJ, Hyun JW. Fisetin induces apoptosis in human nonsmall lung cancer cells via a mitochondria-mediated pathway. In Vitro Cell Dev Biol Anim 2015; 51 (03) 300-309
• 36 Kim JY, Jeon YK, Jeon W, Nam MJ. Fisetin induces apoptosis in Huh-7 cells via downregulation of BIRC8 and Bcl2L2. Food Chem Toxicol 2010; 48 (8-9): 2259-2264 [Internet]
• 37 Jang KY, Jeong SJ, Kim SH. et al. Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells. Cancer Lett 2012; 319 (02) 197-202 [Internet]
• 38 Lee WR, Shen SC, Lin HY, Hou WC, Yang LL, Chen YC. Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)-dependent endonuclease. Biochem Pharmacol 2002; 63 (02) 225-236
• 39 Yi C, Zhang Y, Yu Z. et al. Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways. PLoS One 2014; 9 (07) e99943
• 40 Lin MT, Lin CL, Lin TY. et al. Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway. Tumour Biol 2016; 37 (05) 6987-6996
• 41 Wu MS, Lien GS, Shen SC, Yang LY, Chen YC. N-acetyl-L-cysteine enhances fisetin-induced cytotoxicity via induction of ROS-independent apoptosis in human colonic cancer cells. Mol Carcinog 2014; 53 (Suppl. 01) E119-E129
• 42 Adan A, Baran Y. Fisetin and hesperetin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling. Tumour Biol 2016; 37 (05) 5781-5795
• 43 Ying TH, Yang SF, Tsai SJ. et al. Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2-mediated activation of caspase-8-/caspase-3-dependent pathway. Arch Toxicol 2012; 86 (02) 263-273
• 44 Murtaza I, Adhami VM, Hafeez BB, Saleem M, Mukhtar H. Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-kappaB. Int J Cancer 2009; 125 (10) 2465-2473
• 45 Sung B, Pandey MK, Aggarwal BB. Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IkappaBalpha kinase activation. Mol Pharmacol 2007; 71 (06) 1703-1714
• 46 Li J, Cheng Y, Qu W. et al. Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol 2011; 108 (02) 84-93
• 47 Li J, Qu W, Cheng Y. et al. The inhibitory effect of intravesical fisetin against bladder cancer by induction of p53 and down-regulation of NF-kappa B pathways in a rat bladder carcinogenesis model. Basic Clin Pharmacol Toxicol 2014; 115 (04) 321-329
• 48 Suh Y, Afaq F, Johnson JJ, Mukhtar H. A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis 2009; 30 (02) 300-307
• 49 Han DC. us cr ip t Ac ce Disclosure of Potential Conflicts of Interest: us cr ip t Ac ce. 2015
• 50 Kim TW. Fisetin, an anti-inflammatory agent, overcomes radioresistance by activating the PERK-ATF4-CHOP axis in liver cancer. Int J Mol Sci 2023; 24 (10) 9076
• 51 Ragelle H, Crauste-Manciet S, Seguin J. et al. Nanoemulsion formulation of fisetin improves bioavailability and antitumour activity in mice. Int J Pharm 2012; 427 (02) 452-459
• 52 Li L, Wang M, Yang H. et al. Fisetin inhibits trypsin activity and suppresses the growth of colorectal cancer in vitro and in vivo. Nat Prod Commun 2022; 17 (08) 1934
• 53 Jia S, Xu X, Zhou S, Chen Y, Ding G, Cao L. Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress- and mitochondrial stress-dependent pathways. Cell Death Dis 2019; 10 (02) 142
• 54 Li J, Gong X, Jiang R. et al. Fisetin inhibited growth and metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via PTEN/Akt/GSK3β signal pathway. Front Pharmacol 2018; 9: 772
• 55 Sundarraj K, Raghunath A, Perumal E. A review on the chemotherapeutic potential of fisetin: in vitro evidences. Biomed Pharmacother 2018; 97: 928-940 [Internet]
• 56 Lall RK, Syed DN, Adhami VM, Khan MI, Mukhtar H. Dietary polyphenols in prevention and treatment of prostate cancer. Int J Mol Sci 2015; 16 (02) 3350-3376
• 57 Lall RK, Adhami VM, Mukhtar H. Dietary flavonoid fisetin for cancer prevention and treatment. Mol Nutr Food Res 2016; 60 (06) 1396-1405
• 58 Ravichandran N, Suresh G, Ramesh B, Manikandan R, Choi YW, Vijaiyan Siva G. Fisetin modulates mitochondrial enzymes and apoptotic signals in benzo(a)pyrene-induced lung cancer. Mol Cell Biochem 2014; 390 (1-2): 225-234
• 59 Ravichandran N, Suresh G, Ramesh B, Siva GV. Fisetin, a novel flavonol attenuates benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. Food Chem Toxicol 2011; 49 (05) 1141-1147 [Internet]
• 60 Khan N, Afaq F, Khusro FH, Mustafa Adhami V, Suh Y, Mukhtar H. Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int J Cancer 2012; 130 (07) 1695-1705
• 61 Touil YS, Seguin J, Scherman D, Chabot GG. Improved antiangiogenic and antitumour activity of the combination of the natural flavonoid fisetin and cyclophosphamide in Lewis lung carcinoma-bearing mice. Cancer Chemother Pharmacol 2011; 68 (02) 445-455
• 62 Khan N, Asim M, Afaq F, Abu Zaid M, Mukhtar H. A novel dietary flavonoid fisetin inhibits androgen receptor signaling and tumor growth in athymic nude mice. Cancer Res 2008; 68 (20) 8555-8563
• 63 Suh Y, Afaq F, Khan N, Johnson JJ, Khusro FH, Mukhtar H. Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis 2010; 31 (08) 1424-1433
• 64 Szliszka E, Helewski KJ, Mizgala E, Krol W. The dietary flavonol fisetin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells. Int J Oncol 2011; 39 (04) 771-779
• 65 Hill CUFK, Saad SEA, Britton RG. et al. Inhibition of prostate cancer cell growth by 3′,4′,5′-trimethoxyflavonol (TMFol). Cancer Chemother Pharmacol 2015; 76 (01) 179-185
• 66 Mukhtar E, Adhami VM, Sechi M, Mukhtar H. Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells. Cancer Lett 2015; 367 (02) 173-183 [Internet]
• 67 Kumagai A, Horike N, Satoh Y. et al. A potent inhibitor of SIK2, 3, 3′, 7-trihydroxy-4′-methoxyflavon (4′-O-methylfisetin), promotes melanogenesis in B16F10 melanoma cells. PLoS One 2011; 6 (10) e26148
• 68 Pal HC, Athar M, Elmets CA, Afaq F. Fisetin inhibits UVB-induced cutaneous inflammation and activation of PI3K/AKT/NFκB signaling pathways in SKH-1 hairless mice. Photochem Photobiol 2015; 91 (01) 225-234
• 69 Pal HC, Sharma S, Strickland LR. et al. Fisetin inhibits human melanoma cell invasion through promotion of mesenchymal to epithelial transition and by targeting MAPK and NFκB signaling pathways. PLoS One 2014; 9 (01) e86338
• 70 Syed DN, Lall RK, Chamcheu JC, Haidar O, Mukhtar H. Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma. Arch Biochem Biophys 2014; 563: 108-117 [Internet]
• 71 Pal HC, Baxter RD, Hunt KM. et al. Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells. Oncotarget 2015; 6 (29) 28296-28311
• 72 Center MM, Jemal A, Smith RA. et al. Worldwide variations in colorectal cancer. Dis Colon Rectum 2010; 53: 1099
• 73 Chen WS, Lee YJ, Yu YC. et al. Enhancement of p53-mutant human colorectal cancer cells radiosensitivity by flavonoid fisetin. Int J Radiat Oncol Biol Phys 2010; 77 (05) 1527-1535
• 74 Chen Y, Wu Q, Song L. et al. Polymeric micelles encapsulating fisetin improve the therapeutic effect in colon cancer. ACS Appl Mater Interfaces 2015; 7 (01) 534-542
• 75 Kamat AM, Hahn NM, Efstathiou JA. et al. Bladder cancer. Lancet 2016; 388 (10061): 2796-2810
• 76 Crocetto F, di Zazzo E, Buonerba C. et al. Kaempferol, myricetin and fisetin in prostate and bladder cancer: a systematic review of the literature. Nutrients 2021; 13 (11) 1-14
• 77 Kubina R, Krzykawski K, Kabała-Dzik A, Wojtyczka RD, Chodurek E, Dziedzic A. Fisetin, a potent anticancer flavonol exhibiting cytotoxic activity against neoplastic malignant cells and cancerous conditions: a scoping, comprehensive review. Nutrients 2022; 14 (13) 14
• 78 Cowin P, Rowlands TM, Hatsell SJ. Cadherins and catenins in breast cancer. Curr Opin Cell Biol 2005; 17 (05) 499-508
• 79 Yang PM, Tseng HH, Peng CW, Chen WS, Chiu SJ. Dietary flavonoid fisetin targets caspase-3-deficient human breast cancer MCF-7 cells by induction of caspase-7-associated apoptosis and inhibition of autophagy. Int J Oncol 2012; 40 (02) 469-478
• 80 López-Lázaro M, Willmore E, Austin CA. The dietary flavonoids myricetin and fisetin act as dual inhibitors of DNA topoisomerases I and II in cells. Mutat Res 2010; 696 (01) 41-47
• 81 Adan A, Baran Y. The pleiotropic effects of fisetin and hesperetin on human acute promyelocytic leukemia cells are mediated through apoptosis, cell cycle arrest, and alterations in signaling networks. Tumour Biol 2015; 36 (11) 8973-8984
• 82 Elmore-meegan MK, Mangaj A. For personal use. Only reproduce with permission from The Lancet. Cervical Cancer 2018; 361: 2217-2225
• 83 Adhami VM, Bailey HH, Mukhtar H. Cancer chemoprevention is not a failure. Carcinogenesis 2014; 35 (09) 2154-2155
• 84 Kubina R, Krzykawski K, Kabała-Dzik A, Wojtyczka RD, Chodurek E, Dziedzic A. Fisetin, a potent anticancer flavonol exhibiting cytotoxic activity against neoplastic malignant cells and cancerous conditions: a scoping, comprehensive review. Nutrients 2022; 14 (13) 2604
• 85 Khan N, Syed DN, Ahmad N, Mukhtar H. Fisetin: a dietary antioxidant for health promotion. Antioxid Redox Signal 2013; 19 (02) 151-162
• 86 Fernández-Arroyo S, Herranz-López M, Beltrán-Debón R. et al. Bioavailability study of a polyphenol-enriched extract from Hibiscus sabdariffa in rats and associated antioxidant status. Mol Nutr Food Res 2012; 56 (10) 1590-1595
• 87 van Wyk BE, Albrecht C. A review of the taxonomy, ethnobotany, chemistry and pharmacology of Sutherlandia frutescens (Fabaceae). J Ethnopharmacol 2008; 119 (03) 620-629
• 88 Singh S, Singh AK, Garg G, Rizvi SI. Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration. Life Sci 2018; 193: 171-179
• 89 Imran M, Saeed F, Gilani SA. et al. Fisetin: an anticancer perspective. Food Sci Nutr 2020; 9 (01) 3-16
• 90 McMichael AJ. Food, nutrition, physical activity and cancer prevention. Authoritative report from World Cancer Research Fund provides global update. Public Health Nutr 2008; 11 (07) 762-763
• 91 Kumar N. Challenges and opportunities in drug discovery and development. Curr Sci 2014; 107: 1367