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Review

Cancer Protective Role of Selected Dietary Polyphenols via Modulating Keap1/Nrf2/ARE and Interconnected Signaling Pathways

, , , , &
Pages 1065-1102 | Received 23 Aug 2022, Accepted 16 Feb 2023, Published online: 20 Apr 2023

References

  • Chio IIC, Tuveson DA. ROS in cancer: the burning question. Trends Mol Med. 2017;23(5):411–29. doi:10.1016/j.molmed.2017.03.004.
  • Chun K-S, Raut PK, Kim D-H, Surh Y-J. Role of chemopreventive phytochemicals in NRF2-mediated redox homeostasis in humans. Free Radic Biol Med. 2021;172:699–715. doi:10.1016/j.freeradbiomed.2021.06.031.
  • Mandelker L. Introduction to oxidative stress and mitochondrial dysfunction. Vet Clin North Am Small Anim Pract. 2008;38(1):1–30, v. doi:10.1016/j.cvsm.2007.10.005.
  • Moloney JN, Cotter TG, ROS signalling in the biology of cancer. Semin Cell Dev Biol. 2018;80:50–64. 10.1016/j.semcdb.2017.05.023
  • Klaunig JE, Wang Z. Oxidative stress in carcinogenesis. Curr Opin Toxicol. 2018;7:116–21. doi:10.1016/j.cotox.2017.11.014.
  • Klaunig JE, Kamendulis LM, Hocevar BA. Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol. 2010;38(1):96–109. doi:10.1177/0192623309356453.
  • Noda N, Wakasugi H. Cancer and oxidative stress. Japan Med Assoc J. 2001;44(12):535–9.
  • Sosa V, Moliné T, Somoza R, Paciucci R, Kondoh H, LLeonart ME. Oxidative stress and cancer: an overview. Ageing Res Rev. 2013;12(1):376–90. doi:10.1016/j.arr.2012.10.004.
  • Shaw P, Chattopadhyay A. Nrf2–ARE signaling in cellular protection: mechanism of action and the regulatory mechanisms. J Cell Physiol. 2020;235(4):3119–30. doi:10.1002/jcp.29219.
  • Liu X-F, Hao J-L, Xie T, Malik TH, Lu C-B, Liu C, Shu C, Lu C-W, Zhou D-D. Nrf2 as a target for prevention of age‐related and diabetic cataracts by against oxidative stress. Aging Cell. 2017;16(5):934–42. doi:10.1111/acel.12645.
  • Kobayashi M, Yamamoto M. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul. 2006;46(1):113–40. 10.1016/j.advenzreg.2006.01.007
  • Kim HM, Han JW, Chan JY. Nuclear factor erythroid-2 like 1 (NFE2L1): structure, function and regulation. Gene. 2016;584(1):17–25. doi:10.1016/j.gene.2016.03.002.
  • Dodson M, De La Vega MR, Cholanians AB, Schmidlin CJ, Chapman E, Zhang DD. Modulating NRF2 in disease: timing is everything. Annu Rev Pharmacol Toxicol. 2019;59:555–75. doi:10.1146/annurev-pharmtox-010818-021856.
  • He F, Ru X, Wen T. NRF2, a transcription factor for stress response and beyond. IJMS. 2020;21(13):4777. doi:10.3390/ijms21134777.
  • Ojo OA, Ajiboye B, Fadaka A, Taro P, Shariati MA. Nrf2-Keap1 activation, a promising strategy in the prevention of cancer. FRA. 2017;7(1):1–7. doi:10.5530/fra.2017.1.1.
  • Tebay LE, Robertson H, Durant ST, Vitale SR, Penning TM, Dinkova-Kostova AT, Hayes JD. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med. 2015;88(Pt B):108–46. 10.1016/j.freeradbiomed.2015.06.021
  • Zhou S, Ye W, Zhang M, Liang J. The effects of nrf2 on tumor angiogenesis: a review of the possible mechanisms of action. Crit Rev Eukaryot Gene Expr. 2012;22(2):149–60. doi:10.1615/critreveukargeneexpr.v22.i2.60.
  • Lin T-Y, Cantley LC, DeNicola GM. NRF2 rewires cellular metabolism to support the antioxidant response. In: Morales-Gonzalez JA, Morales-Gonzalez A and Madrigal-Santillan EO, editors. A master regulator of oxidative stress - the transcription factor Nrf2. London: InTechOpen; 2016. p. 107–8.
  • Stewart JD, Hengstler JG, Bolt HM. Control of oxidative stress by the Keap1-Nrf2 pathway. Arch Toxicol. 2011;85(4):239. doi:10.1007/s00204-011-0694-1.
  • Giudice A, Montella M. Activation of the Nrf2–ARE signaling pathway: a promising strategy in cancer prevention. Bioessays. 2006;28(2):169–81. doi:10.1002/bies.20359.
  • Qin S, Deng F, Wu W, Jiang L, Yamashiro T, Yano S, Hou D-X. Baicalein modulates Nrf2/Keap1 system in both Keap1-dependent and Keap1-independent mechanisms. Arch Biochem Biophys. 2014;559:53–61. doi:10.1016/j.abb.2014.03.011.
  • Xiang M, Namani A, Wu S, Wang X. Nrf2: bane or blessing in cancer? J Cancer Res Clin Oncol. 2014;140(8):1251–9. doi:10.1007/s00432-014-1627-1.
  • Robledinos-Antón N, Fernández-Ginés R, Manda G, Cuadrado A. Activators and inhibitors of NRF2: a review of their potential for clinical development. Oxid Med Cell Longev. 2019;2019:1–20. doi:10.1155/2019/9372182.
  • Schmidlin CJ, Dodson MB, Madhavan L, Zhang DD. Redox regulation by NRF2 in aging and disease. Free Radic Biol Med. 2019;134:702–7. doi:10.1016/j.freeradbiomed.2019.01.016.
  • Kensler TW, Wakabayashi N. Nrf2: friend or foe for chemoprevention? Carcinogenesis. 2010;31(1):90–9. doi:10.1093/carcin/bgp231.
  • Smith RE, Tran K, Smith CC, McDonald M, Shejwalkar P, Hara K. The role of the Nrf2/ARE antioxidant system in preventing cardiovascular diseases. Diseases. 2016;4(4):34. doi:10.3390/diseases4040034.
  • McWalter GK, Higgins LG, McLellan LI, Henderson CJ, Song L, Thornalley PJ, Itoh K, Yamamoto M, Hayes JD. Transcription factor Nrf2 is essential for induction of NAD (P) H: quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. J Nutr. 2004;134(12 Suppl):3499S–506S. doi:10.1093/jn/134.12.3499S.
  • Marampon F, Codenotti S, Megiorni F, Del Fattore A, Camero S, Gravina GL, Festuccia C, Musio D, De Felice F, Nardone V, et al. NRF2 orchestrates the redox regulation induced by radiation therapy, sustaining embryonal and alveolar rhabdomyosarcoma cells radioresistance. J Cancer Res Clin Oncol. 2019;145(4):881–93. doi:10.1007/s00432-019-02851-0.
  • Su Z-Y, Shu L, Khor TO, Lee JH, Fuentes F, Kong A-NT. A perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, nrf2, and epigenomics. Top Curr Chem. 2012;329:133–62. doi:10.1007/128_2012_340.
  • Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401–26. doi:10.1146/annurev-pharmtox-011112-140320.
  • de Freitas Silva M, Pruccoli L, Morroni F, Sita G, Seghetti F, Viegas C, Tarozzi A. The Keap1/Nrf2-ARE pathway as a pharmacological target for chalcones. Molecules. 2018;23(7):1803. 10.3390/molecules23071803
  • Roque AT, Gambeloni RZ, Felitti S, Ribeiro ML, Santos JC. Inflammation-induced oxidative stress in breast cancer patients. Med Oncol. 2015;32(12):1–4. doi:10.1007/s12032-015-0709-5.
  • Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell. 2020;38(2):167–97. doi:10.1016/j.ccell.2020.06.001.
  • Siraj MA, Islam MA, Al Fahad MA, Kheya HR, Xiao J, Simal-Gandara J. Cancer chemopreventive role of dietary terpenoids by modulating keap1-Nrf2-ARE signaling system—A comprehensive update. Appl Sci. 2021;11(22):10806. 10.3390/app112210806
  • Wakabayashi N, Shin S, Slocum SL, Agoston ES, Wakabayashi J, Kwak M-K, Misra V, Biswal S, Yamamoto M, Kensler TW. Regulation of notch1 signaling by nrf2: implications for tissue regeneration. Sci Signal. 2010;3(130):ra52–ra. 10.1126/scisignal.2000762
  • Malhotra D, Portales-Casamar E, Singh A, Srivastava S, Arenillas D, Happel C, Shyr C, Wakabayashi N, Kensler TW, Wasserman WW, et al. Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res. 2010;38(17):5718–34. 10.1093/nar/gkq212
  • Niture SK, Jaiswal AK. Nrf2-induced antiapoptotic Bcl-xL protein enhances cell survival and drug resistance. Free Radic Biol Med. 2013;57:119–31. 10.1016/j.freeradbiomed.2012.12.014
  • Li J, Lee J-M, Johnson JA. Microarray analysis reveals an antioxidant responsive element-driven gene set involved in conferring protection from an oxidative stress-induced apoptosis in IMR-32 cells. J Biol Chem. 2002;277(1):388–94. 10.1074/jbc.M109380200
  • Niso-Santano M, González-Polo RA, Bravo-San Pedro JM, Gómez-Sánchez R, Lastres-Becker I, Ortiz-Ortiz MA, Soler G, Morán JM, Cuadrado A, Fuentes JM, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), et al. Activation of apoptosis signal-regulating kinase 1 is a key factor in paraquat-induced cell death: modulation by the Nrf2/Trx axis. Free Radic Biol Med. 2010;48(10):1370–81. 10.1016/j.freeradbiomed.2010.02.024
  • Oh E-T, Kim J-w, Kim JM, Kim SJ, Lee J-S, Hong S-S, Goodwin J, Ruthenborg RJ, Jung MG, Lee H-J, et al. NQO1 inhibits proteasome-mediated degradation of HIF-1α. Nat Commun. 2016;7(1):1–14. 10.1038/ncomms13593
  • Arfmann-Knübel S, Struck B, Genrich G, Helm O, Sipos B, Sebens S, Schäfer H. The crosstalk between Nrf2 and TGF-β1 in the epithelial-mesenchymal transition of pancreatic duct epithelial cells. PLoS One. 2015;10(7):e0132978. 10.1371/journal.pone.0132978
  • Zhao Q, Mao A, Guo R, Zhang L, Yan J, Sun C, Tang J, Ye Y, Zhang Y, Zhang H, et al. Suppression of radiation-induced migration of non-small cell lung cancer through inhibition of Nrf2-Notch Axis. Oncotarget. 2017;8(22):36603–13. 10.18632/oncotarget.16622
  • Zhou W, Mo X, Cui W, Zhang Z, Li D, Li L, Xu L, Yao H, Gao J. Nrf2 inhibits epithelial-mesenchymal transition by suppressing snail expression during pulmonary fibrosis. Sci Rep. 2016;6(1):1–10. 10.1038/srep38646
  • Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014;39(4):199–218. 10.1016/j.tibs.2014.02.002
  • de la Vega MR, Chapman E, Zhang DD. NRF2 and the hallmarks of cancer. Cancer Cell. 2018;34(1):21–43. 10.1016/j.ccell.2018.03.022
  • Song M-Y, Lee D-Y, Chun K-S, Kim E-H. The role of NRF2/KEAP1 signaling pathway in cancer metabolism. IJMS. 2021;22(9):4376. doi:10.3390/ijms22094376.
  • Wang Y-Y, Chen J, Liu X-M, Zhao R, Zhe H. Nrf2-mediated metabolic reprogramming in cancer. Oxid Med Cell Longev. 2018;2018:1–7. doi:10.1155/2018/9304091.
  • Giudice A, Arra C, Turco MC. Review of molecular mechanisms involved in the activation of the Nrf2-ARE signaling pathway by chemopreventive agents. Methods Mol Biol. 2010;647:37–74. doi:10.1007/978-1-60761-738-9_3.
  • Kaspar JW, Niture SK, Jaiswal AK. Nrf2: INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med. 2009;47(9):1304–9. doi:10.1016/j.freeradbiomed.2009.07.035.
  • Kensler TW, Curphey TJ, Maxiutenko Y, Roebuck BD. Chemoprotection by organosulfur inducers of phase 2 enzymes: dithiolethiones and dithiins. Drug Metabol Drug Interact. 2000;17(1–4):3–22. doi:10.1515/dmdi.2000.17.1-4.3.
  • Chen C, Pung D, Leong V, Hebbar V, Shen G, Nair S, Li W, Kong A-NT. Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: effect of chemical structure and stress signals. Free Radic Biol Med. 2004;37(10):1578–90. doi:10.1016/j.freeradbiomed.2004.07.021.
  • Melkamu T, Zhang X, Tan J, Zeng Y, Kassie F. Alteration of microRNA expression in vinyl carbamate-induced mouse lung tumors and modulation by the chemopreventive agent indole-3-carbinol. Carcinogenesis. 2010;31(2):252–8. 10.1093/carcin/bgp208
  • Higgins LG, Cavin C, Itoh K, Yamamoto M, Hayes JD. Induction of cancer chemopreventive enzymes by coffee is mediated by transcription factor Nrf2. Evidence that the coffee-specific diterpenes cafestol and kahweol confer protection against acrolein. Toxicol Appl Pharmacol. 2008;226(3):328–37. doi:10.1016/j.taap.2007.09.018.
  • Cavin C, Holzhaeuser D, Scharf G, Constable A, Huber WW, Schilter B. Cafestol and kahweol, two coffee specific diterpenes with anticarcinogenic activity. Food Chem Toxicol. 2002;40(8):1155–63. doi:10.1016/s0278-6915(02)00029-7.
  • Nakamura Y, Yoshida C, Murakami A, Ohigashi H, Osawa T, Uchida K. Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes. FEBS Lett. 2004;572(1–3):245–50.
  • Jeong W-S, Jun M, Kong A-NT. Nrf2: a potential molecular target for cancer chemoprevention by natural compounds. Antioxid Redox Signal. 2006;8(1–2):99–106. doi:10.1089/ars.2006.8.99.
  • Stevens JF, Page JE. Xanthohumol and related prenylflavonoids from hops and beer: to your good health!. Phytochemistry. 2004;65(10):1317–30.
  • Yan C, Sun W, Wang X, Long J, Liu X, Feng Z, Liu J. Punicalagin attenuates palmitate‐induced lipotoxicity in HepG2 cells by activating the Keap1‐Nrf2 antioxidant defense system. Mol Nutr Food Res. 2016;60(5):1139–49. doi:10.1002/mnfr.201500490.
  • Seeram N, Lee R, Hardy M, Heber D. Rapid large scale purification of ellagitannins from pomegranate husk, a by-product of the commercial juice industry. Purif Technol. 2005;41(1):49–55. doi:10.1016/j.seppur.2004.04.003.
  • Salehi B, Mishra AP, Nigam M, Sener B, Kilic M, Sharifi-Rad M, et al. Resveratrol: a double-edged sword in health benefits. Biomedicines. 2018;6(3):91.
  • De Vincenzi M, Silano M, Stacchini P, Scazzocchio B. Constituents of aromatic plants: I. Methyleugenol. Fitoterapia. 2000;71(2):216–21. doi:10.1016/s0367-326x(99)00150-1.
  • Tang F, Chen F, Ling X, Huang Y, Zheng X, Tang Q, et al. Inhibitory effect of methyleugenol on IgE-mediated allergic inflammation in RBL-2H3 cells. Mediators Inflamm. 2015;2015:463530. doi:10.1155/2015/463530.
  • Yano S, Suzuki Y, Yuzurihara M, Kase Y, Takeda S, Watanabe S, Aburada M, Miyamoto K-I. Antinociceptive effect of methyleugenol on formalin-induced hyperalgesia in mice. Eur J Pharmacol. 2006;553(1–3):99–103. doi:10.1016/j.ejphar.2006.09.020.
  • Suekawa M, Ishige A, Yuasa K, Sudo K, Aburada M, Hosoya E. Pharmacological studies on ginger. I. Pharmacological actions of pungent constituents,(6)-gingerol and (6)-shogaol. J Pharmacobiodyn. 1984;7(11):836–48. doi:10.1248/bpb1978.7.836.
  • Liu D, Wang H, Zhang Y, Zhang Z. Protective effects of chlorogenic acid on cerebral ischemia/reperfusion injury rats by regulating oxidative stress-related Nrf2 pathway. Drug Des Devel Ther. 2020;14:51–60. doi:10.2147/dddt.S228751.
  • Mancuso C, Santangelo R. Ferulic acid: pharmacological and toxicological aspects. Food Chem Toxicol. 2014;65:185–95. doi:10.1016/j.fct.2013.12.024.
  • Hadad N, Levy R. The synergistic anti-inflammatory effects of lycopene, lutein, β-carotene, and carnosic acid combinations via redox-based inhibition of NF-κB signaling. Free Radic Biol Med. 2012;53(7):1381–91. doi:10.1016/j.freeradbiomed.2012.07.078.
  • Frankel EN, Huang S-W, Aeschbach R, Prior E. Antioxidant activity of a rosemary extract and its constituents, carnosic acid, carnosol, and rosmarinic acid, in bulk oil and oil-in-water emulsion. J Agric Food Chem. 1996;44(1):131–5. doi:10.1021/jf950374p.
  • Larrosa M, García-Conesa MT, Espín JC, Tomás-Barberán FA. Ellagitannins, ellagic acid and vascular health. Mol Aspects Med. 2010;31(6):513–39. doi:10.1016/j.mam.2010.09.005.
  • Yang J, Pi C, Wang G. Inhibition of PI3K/Akt/mTOR pathway by apigenin induces apoptosis and autophagy in hepatocellular carcinoma cells. Biomed Pharmacother. 2018;103:699–707. doi:10.1016/j.biopha.2018.04.072.
  • Cabrera C, Artacho R, Giménez R. Beneficial effects of green tea—a review. J Am Coll Nutr. 2006;25(2):79–99. doi:10.1080/07315724.2006.10719518.
  • Singh BN, Rawat AKS, Bhagat RM, Singh BR. Black tea: phytochemicals, cancer chemoprevention, and clinical studies. Crit Rev Food Sci Nutr. 2017;57(7):1394–410. doi:10.1080/10408398.2014.994700.
  • Huang Z, Jing X, Sheng Y, Zhang J, Hao Z, Wang Z, Ji L. (-)-Epicatechin attenuates hepatic sinusoidal obstruction syndrome by inhibiting liver oxidative and inflammatory injury. Redox Biol. 2019;22:101117. doi:10.1016/j.redox.2019.101117.
  • Abdulkhaleq LA, Assi MA, Noor MHM, Abdullah R, Saad MZ, Taufiq-Yap YH. Therapeutic uses of epicatechin in diabetes and cancer. Vet World. 2017;10(8):869–72. doi:10.14202/vetworld.2017.869-872.
  • Stuart EC, Scandlyn MJ, Rosengren RJ. Role of epigallocatechin gallate (EGCG) in the treatment of breast and prostate cancer. Life Sci. 2006;79(25):2329–36. doi:10.1016/j.lfs.2006.07.036.
  • 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(9):2243–50. doi:10.1093/jn/130.9.2243.
  • Guo J, Yang G, He Y, Xu H, Fan H, An J, Zhang L, Zhang R, Cao G, Hao D, et al. Involvement of α7nAChR in the protective effects of genistein against β-amyloid-induced oxidative stress in neurons via a PI3K/Akt/Nrf2 pathway-related mechanism. Cell Mol Neurobiol. 2021;41(2):377–93. doi:10.1007/s10571-020-01009-8.
  • Yuan L, Wei S, Wang J, Liu X. Isoorientin induces apoptosis and autophagy simultaneously by reactive oxygen species (ROS)-related p53, PI3K/Akt, JNK, and p38 signaling pathways in HepG2 cancer cells. J Agric Food Chem. 2014;62(23):5390–400. doi:10.1021/jf500903g.
  • Lim JH, Park H-S, Choi J-K, Lee I-S, Choi HJ. Isoorientin induces Nrf2 pathway-driven antioxidant response through phosphatidylinositol 3-kinase signaling. Arch Pharm Res. 2007;30(12):1590–8. doi:10.1007/BF02977329.
  • Ji L-L, Sheng Y-C, Zheng Z-Y, Shi L, Wang Z-T. The involvement of p62–Keap1–Nrf2 antioxidative signaling pathway and JNK in the protection of natural flavonoid quercetin against hepatotoxicity. Free Radic Biol Med. 2015;85:12–23. doi:10.1016/j.freeradbiomed.2015.03.035.
  • Tang X, Wang H, Fan L, Wu X, Xin A, Ren H, Wang XJ. Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs. Free Radic Biol Med. 2011;50(11):1599–609. doi:10.1016/j.freeradbiomed.2011.03.008.
  • Patel K, Patel DK. The beneficial role of rutin, a naturally occurring flavonoid in health promotion and disease prevention: a systematic review and update. In: Watson RR, Preedy VR, editors. Bioactive food as dietary interventions for arthritis and related inflammatory diseases. 2nd ed. Academic Press; 2019. p. 457–79. doi:10.1016/B978-0-12-813820-5.00026-X.
  • Zhang L, Guo Z, Wang Y, Geng J, Han S. The protective effect of kaempferol on heart via the regulation of Nrf2, NF‐κβ, and PI3K/Akt/GSK‐3β signaling pathways in isoproterenol‐induced heart failure in diabetic rats. Drug Dev Res. 2019;80(3):294–309. doi:10.1002/ddr.21495.
  • Krajka-Kuźniak V, Paluszczak J, Baer-Dubowska W. Xanthohumol induces phase II enzymes via Nrf2 in human hepatocytes in vitro. Toxicol In Vitro. 2013;27(1):149–56. doi:10.1016/j.tiv.2012.10.008.
  • Cykowiak M, Krajka-Kuźniak V, Baer-Dubowska W. Combinations of phytochemicals more efficiently than single components activate Nrf2 and induce the expression of antioxidant enzymes in pancreatic cancer cells. Nutr Cancer. 2022;74(3):996–1011. doi:10.1080/01635581.2021.1933097.
  • Cykowiak M, Kleszcz R, Kucińska M, Paluszczak J, Szaefer H, Plewiński A, Piotrowska-Kempisty H, Murias M, Krajka-Kuźniak V. Attenuation of pancreatic cancer in vitro and in vivo via modulation of Nrf2 and NF-κB signaling pathways by natural compounds. Cells. 2021;10(12):3556. doi:10.3390/cells10123556.
  • Benelli R, Venè R, Ciarlo M, Carlone S, Barbieri O, Ferrari N. The AKT/NF-κB inhibitor xanthohumol is a potent anti-lymphocytic leukemia drug overcoming chemoresistance and cell infiltration. Biochem Pharmacol. 2012;83(12):1634–42. 10.1016/j.bcp.2012.03.006
  • Nishimura R, Tabata K, Arakawa M, Ito Y, Kimura Y, Akihisa T, Nagai H, Sakuma A, Kohno H, Suzuki T, et al. Isobavachalcone, a chalcone constituent of Angelica keiskei, induces apoptosis in neuroblastoma. Biol Pharm Bull. 2007;30(10):1878–83. doi:10.1248/bpb.30.1878.
  • Colgate EC, Miranda CL, Stevens JF, Bray TM, Ho E. Xanthohumol, a prenylflavonoid derived from hops induces apoptosis and inhibits NF-kappaB activation in prostate epithelial cells. Cancer Lett. 2007;246(1–2):201–9.
  • Deeb D, Gao X, Jiang H, Arbab AS, Dulchavsky S, Gautam SC. Growth inhibitory and apoptosis-inducing effects of xanthohumol, a prenylated chalone present in hops, in human prostate cancer cells. Anticancer Res. 2010;30(9):3333–9.
  • Zhang L, Chinnathambi A, Alharbi SA, Veeraraghavan VP, Mohan SK, Zhang G. Punicalagin promotes the apoptosis in human cervical cancer (ME-180) cells through mitochondrial pathway and by inhibiting the NF-kB signaling pathway. Saudi J Biol Sci. 2020;27(4):1100–6. doi:10.1016/j.sjbs.2020.02.015.
  • Huang T, Zhang X, Wang H. Punicalagin inhibited proliferation, invasion and angiogenesis of osteosarcoma through suppression of NF‑κB signaling. Mol Med Rep. 2020;22(3):2386–94. doi:10.3892/mmr.2020.11304.
  • Adams LS, Seeram NP, Aggarwal BB, Takada Y, Sand D, Heber D. Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J Agric Food Chem. 2006;54(3):980–5. doi:10.1021/jf052005r.
  • Berdowska I, Matusiewicz M, Fecka I. Punicalagin in cancer prevention—Via signaling pathways targeting. Nutrients. 2021;13(8):2733. doi:10.3390/nu13082733.
  • Singh B, Shoulson R, Chatterjee A, Ronghe A, Bhat NK, Dim DC, et al. Resveratrol inhibits estrogen-induced breast carcinogenesis through induction of NRF2-mediated protective pathways. Carcinogenesis. 2014;35(8):1872–80.
  • Farkhondeh T, Folgado SL, Pourbagher-Shahri AM, Ashrafizadeh M, Samarghandian S. The therapeutic effect of resveratrol: focusing on the Nrf2 signaling pathway. Biomed Pharmacother. 2020;127:110234. doi:10.1016/j.biopha.2020.110234.
  • Bishayee A, Barnes KF, Bhatia D, Darvesh AS, Carroll RT. Resveratrol suppresses oxidative stress and inflammatory response in diethylnitrosamine-initiated rat hepatocarcinogenesis. Cancer Prev Res (Phila). 2010;3(6):753–63. doi:10.1158/1940-6207.CAPR-09-0171.
  • Benitez DA, Hermoso MA, Pozo‐Guisado E, Fernández‐Salguero PM, Castellón EA. Regulation of cell survival by resveratrol involves inhibition of NFκB‐regulated gene expression in prostate cancer cells. Prostate. 2009;69(10):1045–54.
  • Whitlock NC, Baek SJ. The anticancer effects of resveratrol: modulation of transcription factors. Nutr Cancer. 2012;64(4):493–502. doi:10.1080/01635581.2012.667862.
  • Carter LG, D’Orazio JA, Pearson KJ. Resveratrol and cancer: focus on in vivo evidence. Endocr Relat Cancer. 2014;21(3):R209–25.
  • Yi J-L, Shi S, Shen Y-L, Wang L, Chen H-Y, Zhu J, et al. Myricetin and methyl eugenol combination enhances the anticancer activity, cell cycle arrest and apoptosis induction of cis-platin against HeLa cervical cancer cell lines. Int J Clin Exp Path. 2015;8(2):1116.
  • Yin L, Sun Z, Ren Q, Su X, Zhang D. Methyl eugenol induces potent anticancer effects in RB355 human retinoblastoma cells by inducing autophagy, cell cycle arrest and inhibition of PI3K/mTOR/Akt signalling pathway. J Buon. 2018;23:1174–8.
  • Groh IAM, Chen C, Lüske C, Cartus AT, Esselen M. Plant polyphenols and oxidative metabolites of the herbal alkenylbenzene methyleugenol suppress histone deacetylase activity in human colon carcinoma cells. J Nutr Metab. 2013;2013:821082. doi:10.1155/2013/821082.
  • Ling H, Yang H, Tan SH, Chui WK, Chew EH. 6‐Shogaol, an active constituent of ginger, inhibits breast cancer cell invasion by reducing matrix metalloproteinase‐9 expression via blockade of nuclear factor‐κB activation. Br J Pharmacol. 2010;161(8):1763–77. doi:10.1111/j.1476-5381.2010.00991.x.
  • Hung J-Y, Hsu Y-L, Li C-T, Ko Y-C, Ni W-C, Huang M-S, Kuo P-L. 6-Shogaol, an active constituent of dietary ginger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells. J Agric Food Chem. 2009;57(20):9809–16. doi:10.1021/jf902315e.
  • Saha A, Blando J, Silver E, Beltran L, Sessler J, DiGiovanni J. 6-Shogaol from dried ginger inhibits growth of prostate cancer cells both in vitro and in vivo through inhibition of STAT3 and NF-κB signaling. Cancer Prev Res (Phila). 2014;7(6):627–38. doi:10.1158/1940-6207.CAPR-13-0420.
  • Zhou L, Qi L, Jiang L, Zhou P, Ma J, Xu X, Li P. Antitumor activity of gemcitabine can be potentiated in pancreatic cancer through modulation of TLR4/NF-κB signaling by 6-shogaol. Aaps J. 2014;16(2):246–57. doi:10.1208/s12248-013-9558-3.
  • Ma R-H, Ni Z-J, Zhang F, Zhang Y-Y, Liu M-M, Thakur K, et al. 6-Shogaol mediated ROS production and apoptosis via endoplasmic reticulum and mitochondrial pathways in human endometrial carcinoma Ishikawa cells. J Funct Foods. 2020;74:104178.
  • Ma R-H, Ni Z-J, Thakur K, Cespedes-Acuña CL, Zhang J-G, Wei Z-J. Transcriptome and proteomics conjoint analysis reveal metastasis inhibitory effect of 6-shogaol as ferroptosis activator through the PI3K/AKT pathway in human endometrial carcinoma in vitro and in vivo. Food Chem Toxicol. 2022;170:113499. doi:10.1016/j.fct.2022.113499.
  • Warin RF, Chen H, Soroka DN, Zhu Y, Sang S. Induction of lung cancer cell apoptosis through a p53 pathway by [6]-shogaol and its cysteine-conjugated metabolite M2. J Agric Food Chem. 2014;62(6):1352–62.
  • Boettler U, Volz N, Pahlke G, Teller N, Kotyczka C, Somoza V, Stiebitz H, Bytof G, Lantz I, Lang R, et al. Coffees rich in chlorogenic acid or N‐methylpyridinium induce chemopreventive phase II‐enzymes via the Nrf2/ARE pathway in vitro and in vivo. Mol Nutr Food Res. 2011;55(5):798–802. doi:10.1002/mnfr.201100115.
  • Deka SJ, Gorai S, Manna D, Trivedi V. Evidence of PKC binding and translocation to explain the anticancer mechanism of chlorogenic acid in breast cancer cells. Curr Mol Med. 2017;17(1):79–89. doi:10.2174/1566524017666170209160619.
  • Han D, Chen W, Gu X, Shan R, Zou J, Liu G, Shahid M, Gao J, Han B. Cytoprotective effect of chlorogenic acid against hydrogen peroxide-induced oxidative stress in MC3T3-E1 cells through PI3K/Akt-mediated Nrf2/HO-1 signaling pathway. Oncotarget. 2017;8(9):14680–92. doi:10.18632/oncotarget.14747.
  • Wang X, Liu J, Xie Z, Rao J, Xu G, Huang K, Li W, Yin Z. Chlorogenic acid inhibits proliferation and induces apoptosis in A498 human kidney cancer cells via inactivating PI3K/Akt/mTOR signalling pathway. J Pharm Pharmacol. 2019;71(7):1100–9. doi:10.1111/jphp.13095.
  • Yamagata K, Izawa Y, Onodera D, Tagami M. Chlorogenic acid regulates apoptosis and stem cell marker-related gene expression in A549 human lung cancer cells. Mol Cell Biochem. 2018;441(1–2):9–19. doi:10.1007/s11010-017-3171-1.
  • Hou N, Liu N, Han J, Yan Y, Li J. Chlorogenic acid induces reactive oxygen species generation and inhibits the viability of human colon cancer cells. Anticancer Drugs. 2017;28(1):59–65. doi:10.1097/cad.0000000000000430.
  • Yan Y, Li J, Han J, Hou N, Song Y, Dong L. Chlorogenic acid enhances the effects of 5-fluorouracil in human hepatocellular carcinoma cells through the inhibition of extracellular signal-regulated kinases. Anticancer Drugs. 2015;26(5):540–6. doi:10.1097/cad.0000000000000218.
  • Wang L, Du H, Chen P. Chlorogenic acid inhibits the proliferation of human lung cancer A549 cell lines by targeting annexin A2 in vitro and in vivo. Biomed Pharmacother. 2020;131:110673.
  • Yan Y, Liu N, Hou N, Dong L, Li J. Chlorogenic acid inhibits hepatocellular carcinoma in vitro and in vivo. J Nutr Biochem. 2017;46:68–73. doi:10.1016/j.jnutbio.2017.04.007.
  • Zeng A, Liang X, Zhu S, Liu C, Wang S, Zhang Q, Zhao J, Song L. Chlorogenic acid induces apoptosis, inhibits metastasis and improves antitumor immunity in breast cancer via the NF‑κB signaling pathway. Oncol Rep. 2021;45(2):717–27. doi:10.3892/or.2020.7891.
  • Li Y, Li X, Cuiping C, Pu R, Weihua Y. Study on the anticancer effect of an astragaloside-and chlorogenic acid-containing herbal medicine (RLT-03) In breast cancer. Evid-based Complement Altern Med. 2020;2020:1515081. doi:10.1155/2020/1515081.
  • Gao J, Yu H, Guo W, Kong Y, Gu L, Li Q, Yang S, Zhang Y, Wang Y. The anticancer effects of ferulic acid is associated with induction of cell cycle arrest and autophagy in cervical cancer cells. Cancer Cell Int. 2018;18:102. doi:10.1186/s12935-018-0595-y.
  • Roy N, Narayanankutty A, Nazeem PA, Valsalan R, Babu TD, Mathew D. Plant phenolics ferulic acid and P-coumaric acid inhibit colorectal cancer cell proliferation through EGFR down-regulation. Asian Pac J Cancer Prev: APJCP. 2016;17(8):4019–23.
  • Eroğlu C, Seçme M, Bağcı G, Dodurga Y. Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines. Tumour Biol. 2015;36(12):9437–46. doi:10.1007/s13277-015-3689-3.
  • Zhang X, Lin D, Jiang R, Li H, Wan J, Li H. Ferulic acid exerts antitumor activity and inhibits metastasis in breast cancer cells by regulating epithelial to mesenchymal transition. Oncol Rep. 2016;36(1):271–8. doi:10.3892/or.2016.4804.
  • El-Gogary RI, Nasr M, Rahsed LA, Hamzawy MA. Ferulic acid nanocapsules as a promising treatment modality for colorectal cancer: preparation and in vitro/in vivo appraisal. Life Sci. 2022;298:120500. 10.1016/j.lfs.2022.120500
  • Yang G-W, Jiang J-S, Lu W-Q. Ferulic acid exerts anti-angiogenic and anti-tumor activity by targeting fibroblast growth factor receptor 1-mediated angiogenesis. Int J Mol Sci. 2015;16(10):24011–31.
  • Barni MV, Carlini MJ, Cafferata EG, Puricelli L, Moreno S. Carnosic acid inhibits the proliferation and migration capacity of human colorectal cancer cells. Oncol Rep. 2012;27(4):1041–8. doi:10.3892/or.2012.1630.
  • Khella KF, Abd E, Maksoud AI, Hassan A, Abdel-Ghany SE, Elsanhoty RM, Aladhadh MA, et al. Carnosic acid encapsulated in albumin nanoparticles induces apoptosis in breast and colorectal cancer cells. Molecules. 2022;27(13):4102.
  • Tang B, Tang F, Wang Z, Qi G, Liang X, Li B, Yuan S, Liu J, Yu S, He S, et al. Upregulation of Akt/NF-κB-regulated inflammation and Akt/Bad-related apoptosis signaling pathway involved in hepatic carcinoma process: suppression by carnosic acid nanoparticle. Int J Nanomedicine. 2016;11:6401–20. doi:10.2147/ijn.S101285.
  • El-Huneidi W, Bajbouj K, Muhammad JS, Vinod A, Shafarin J, Khoder G, et al. Carnosic acid induces apoptosis and inhibits Akt/mTOR signaling in human gastric cancer cell lines. Pharmaceuticals (Basel, Switzerland). 2021;14(3):230–239. doi:10.3390/ph14030230.
  • Kim D-H, Park K-W, Chae IG, Kundu J, Kim E-H, Kundu JK, Chun K-S. Carnosic acid inhibits STAT3 signaling and induces apoptosis through generation of ROS in human colon cancer HCT116 cells. Mol Carcinog. 2016;55(6):1096–110. doi:10.1002/mc.22353.
  • Su K, Wang CF, Zhang Y, Cai YJ, Zhang YY, Zhao Q. The inhibitory effects of carnosic acid on cervical cancer cells growth by promoting apoptosis via ROS-regulated signaling pathway. Biomed Pharmacother. 2016;82:180–91. doi:10.1016/j.biopha.2016.04.056.
  • Sang Y, Zhang F, Wang H, Yao J, Chen R, Zhou Z, Yang K, Xie Y, Wan T, Ding H, et al. Apigenin exhibits protective effects in a mouse model of d-galactose-induced aging via activating the Nrf2 pathway. Food Funct. 2017;8(6):2331–40. doi:10.1039/c7fo00037e.
  • Liu X, Dong S, Dong M, Li Y, Sun Z, Zhang X, et al. Transferrin-conjugated liposomes loaded with carnosic acid inhibit liver cancer growth by inducing mitochondria-mediated apoptosis. Int J Pharm. 2021;607:121034.
  • Yan M, Vemu B, Veenstra J, Petiwala SM, Johnson JJ. Carnosol, a dietary diterpene from rosemary (Rosmarinus officinalis) activates Nrf2 leading to sestrin 2 induction in colon cells. Integr Mol Med. 2018;5(4). doi:10.15761/imm.1000335.
  • Johnson JJ, Syed DN, Heren CR, Suh Y, Adhami VM, Mukhtar H. Carnosol, a dietary diterpene, displays growth inhibitory effects in human prostate cancer PC3 cells leading to G2-phase cell cycle arrest and targets the 5’-AMP-activated protein kinase (AMPK) pathway. Pharm Res. 2008;25(9):2125–34. doi:10.1007/s11095-008-9552-0.
  • Alsamri H, Hasasna E, Al H, Dhaheri Y, Eid AH, Attoub S, Iratni R. Carnosol, a natural polyphenol, inhibits migration, metastasis, and tumor growth of breast cancer via a ROS-dependent proteasome degradation of STAT3. Front Oncol. 2019;9:743. doi:10.3389/fonc.2019.00743.
  • Tong XP, Ma YX, Quan DN, Zhang L, Yan M, Fan XR. Rosemary extracts upregulate Nrf2, Sestrin2, and MRP2 protein level in human hepatoma HepG2 cells. Evid Based Complement Alternat Med. 2017;2017:7359806. doi:10.1155/2017/7359806.
  • Wang Y, Ren F, Li B, Song Z, Chen P, Ouyang L. Ellagic acid exerts antitumor effects via the PI3K signaling pathway in endometrial cancer. J Cancer. 2019;10(15):3303.
  • Wang N, Wang Z-Y, Mo S-L, Loo TY, Wang D-M, Luo H-B, Yang D-P, Chen Y-L, Shen J-G, Chen J-P, et al. Ellagic acid, a phenolic compound, exerts anti-angiogenesis effects via VEGFR-2 signaling pathway in breast cancer. Breast Cancer Res Treat. 2012;134(3):943–55. doi:10.1007/s10549-012-1977-9.
  • Eskandari E, Heidarian E, Amini SA, Saffari-Chaleshtori J. Evaluating the effects of ellagic acid on pSTAT3, pAKT, and pERK1/2 signaling pathways in prostate cancer PC3 cells. J Cancer Res Ther. 2016;12(4):1266–71. doi:10.4103/0973-1482.165873.
  • Cheng H, Lu C, Tang R, Pan Y, Bao S, Qiu Y, et al. Ellagic acid inhibits the proliferation of human pancreatic carcinoma PANC-1 cells in vitro and in vivo. Oncotarget. 2017;8(7):12301.
  • Li TM, Chen GW, Su CC, Lin JG, Yeh CC, Cheng KC, et al. Ellagic acid induced p53/p21 expression, G1 arrest and apoptosis in human bladder cancer T24 cells. Anticancer Res. 2005;25(2a):971–9.
  • Duan J, Li Y, Gao H, Yang D, He X, Fang Y, Zhou G. Phenolic compound ellagic acid inhibits mitochondrial respiration and tumor growth in lung cancer. Food Funct. 2020;11(7):6332–9.
  • Paredes-Gonzalez X, Fuentes F, Su Z-Y, Kong A-NT. Apigenin reactivates Nrf2 anti-oxidative stress signaling in mouse skin epidermal JB6 P + cells through epigenetics modifications. AAPS J. 2014;16(4):727–35.
  • Mahmoudi S, Ghorbani M, Sabzichi M, Ramezani F, Hamishehkar H, Samadi N. Targeted hyaluronic acid-based lipid nanoparticle for apigenin delivery to induce Nrf2-dependent apoptosis in lung cancer cells. J Drug Deliv Sci Technol. 2019;49:268–76. doi:10.1016/j.jddst.2018.11.013.
  • Kaur P, Shukla S, Gupta S. Plant flavonoid apigenin inactivates Akt to trigger apoptosis in human prostate cancer: an in vitro and in vivo study. Carcinogenesis. 2008;29(11):2210–7.
  • Shukla S, Gupta S. Apigenin suppresses insulin‐like growth factor I receptor signaling in human prostate cancer: an in vitro and in vivo study. Mol Carcinog. 2009;48(3):243–52.
  • Chen X, Xu H, Yu X, Wang X, Zhu X, Xu X. Apigenin inhibits in vitro and in vivo tumorigenesis in cisplatin-resistant colon cancer cells by inducing autophagy, programmed cell death and targeting m-TOR/PI3K/Akt signalling pathway. J Buon. 2019;24(2):488–93.
  • Budhraja A, Gao N, Zhang Z, Son Y-O, Cheng S, Wang X, et al. Apigenin induces apoptosis in human leukemia cells and exhibits anti-leukemic activity in vivo. Mol Cancer Ther. 2012;11(1):132–42.
  • Zhang E, Zhang Y, Fan Z, Cheng L, Han S, Che H. Apigenin inhibits histamine-induced cervical cancer tumor growth by regulating estrogen receptor expression. Molecules. 2020;25(8):1960.
  • Khojaste E, Ahmadizadeh C. Catechin metabolites along with curcumin inhibit proliferation and induce apoptosis in cervical cancer cells by regulating VEGF expression in-vitro. Nutr Cancer. 2022;74(3):1048–57.
  • Manikandan R, Beulaja M, Arulvasu C, Sellamuthu S, Dinesh D, Prabhu D. Synergistic anticancer activity of curcumin and catechin: an in vitro study using human cancer cell lines. Microsc Res Tech. 2012;75(2):112–6.
  • Pereyra-Vergara F, Olivares-Corichi IM, Perez-Ruiz AG, Luna-Arias JP, García-Sánchez JR. Apoptosis induced by (−)-epicatechin in human breast cancer cells is mediated by reactive oxygen species. Molecules. 2020;25(5):1020.
  • Rodriguez M, Du G-J, Wang C-Z, Yuan C-S. Panaxadiol’s anticancer activity is enhanced by epicatechin. Am J Chin Med. 2010;38(6):1233–5. doi:10.1142/S0192415X10008597.
  • Horie N, Hirabayashi N, Takahashi Y, Miyauchi Y, Taguchi H, Takeishi K. Synergistic effect of green tea catechins on cell growth and apoptosis induction in gastric carcinoma cells. Biol Pharm Bull. 2005;28(4):574–9. doi:10.1248/bpb.28.574.
  • Chen L, Guo Y, Wu Z, Zhao S, Zhang Z, Zheng F, Sun L, Hao Z, Xu C, Wang T, et al. Epicatechin gallate prevents the de novo synthesis of fatty acid and the migration of prostate cancer cells. Acta Biochim Biophys Sin (Shanghai). 2021;53(12):1662–9. doi:10.1093/abbs/gmab144.
  • Ahmadi N, Mohamed S, Rahman S, Rosli H. R. Epicatechin and scopoletin‐rich Morinda citrifolia leaf ameliorated leukemia via anti‐inflammatory, anti‐angiogenesis, and apoptosis pathways in vitro and in vivo. J Food Biochem. 2019;43(7):e12868.
  • Enkhbat T, Nishi M, Yoshikawa K, Jun H, Tokunaga T, Takasu C, Kashihara H, Ishikawa D, Tominaga M, Shimada M, et al. Epigallocatechin-3-gallate enhances radiation sensitivity in colorectal cancer cells through Nrf2 activation and autophagy. Anticancer Res. 2018;38(11):6247–52. doi:10.21873/anticanres.12980.
  • Datta S, Sinha D. EGCG maintained Nrf2-mediated redox homeostasis and minimized etoposide resistance in lung cancer cells. J Func Foods. 2019;62:103553. doi:10.1016/j.jff.2019.103553.
  • Wang J, Man GCW, Chan TH, Kwong J, Wang CC. A prodrug of green tea polyphenol (–)-epigallocatechin-3-gallate (Pro-EGCG) serves as a novel angiogenesis inhibitor in endometrial cancer. Cancer Lett. 2018;412:10–20. doi:10.1016/j.canlet.2017.09.054.
  • Roy AM, Baliga MS, Katiyar SK. Epigallocatechin-3-gallate induces apoptosis in estrogen receptor–negative human breast carcinoma cells via modulation in protein expression of p53 and Bax and caspase-3 activation. Mol Cancer Ther. 2005;4(1):81–90.
  • Gan R-Y, Li H-B, Sui Z-Q, Corke H. Absorption, metabolism, anti-cancer effect and molecular targets of epigallocatechin gallate (EGCG): an updated review. Crit Rev Food Sci Nutr. 2018;58(6):924–41.
  • Kim N, Lee SH, Son JH, Lee JM, Kang M-J, Kim BH, Lee J-S, Ryu JK, Kim Y-T. Fisetin reduces cell viability through up-regulation of phosphorylation of ERK1/2 in cholangiocarcinoma cells. Anticancer Res. 2016;36(11):6109–16. doi:10.21873/anticanres.11201.
  • Park B-S, Choi N-E, Lee JH, Kang H-M, Yu S-B, Kim H-J, Kang H-K, Kim I-R. Crosstalk between fisetin-induced apoptosis and autophagy in human oral squamous cell carcinoma. J Cancer. 2019;10(1):138–46. doi:10.7150/jca.28500.
  • Sun X, Ma X, Li Q, Yang Y, Xu X, Sun J, et al. Anti‑cancer effects of fisetin on mammary carcinoma cells via regulation of the PI3K/Akt/mTOR pathway: in vitro and in vivo studies. Int J Mol Med. 2018;42(2):811–20.
  • Li J, Cheng Y, Qu W, Sun Y, Wang Z, Wang H, Tian B. 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(2):84–93. doi:10.1111/j.1742-7843.2010.00613.x.
  • 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-κB-signaling pathways. Carcinogenesis. 2009;30(2):300–7.
  • Youns M, Abdel Halim Hegazy W. The natural flavonoid fisetin inhibits cellular proliferation of hepatic, colorectal, and pancreatic cancer cells through modulation of multiple signaling pathways. PLoS One. 2017;12(1):e0169335. doi:10.1371/journal.pone.0169335.
  • 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(5):1049–56.
  • Xiao Y, Liu Y, Gao Z, Li X, Weng M, Shi C, et al. Fisetin inhibits the proliferation, migration and invasion of pancreatic cancer by targeting PI3K/AKT/mTOR signaling. Aging (Albany NY). 2021;13(22):24753.
  • Ying T-H, Yang S-F, Tsai S-J, Hsieh S-C, Huang Y-C, Bau D-T, Hsieh Y-H. 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(2):263–73.
  • Davis JN, Kucuk O, Sarkar FH. Genistein inhibits NF-kB activation in prostate cancer cells. Nutr Cancer. 1999;35(2):167–74. doi:10.1207/S15327914NC352_11.
  • Banerjee S, Zhang Y, Ali S, Bhuiyan M, Wang Z, Chiao PJ, Philip PA, Abbruzzese J, Sarkar FH. Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res. 2005;65(19):9064–72.
  • Pagliacci M, Smacchia M, Migliorati G, Grignani F, Riccardi C, Nicoletti I. Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF-7 human breast cancer cells. Eur J Cancer. 1994;30(11):1675–82. doi:10.1016/0959-8049(94)00262-4.
  • Hsiao YC, Peng SF, Lai KC, Liao CL, Huang YP, Lin CC, et al. Genistein induces apoptosis in vitro and has antitumor activity against human leukemia HL‐60 cancer cell xenograft growth in vivo. Environ Toxicol. 2019;34(4):443–56.
  • Wang Y, Wang H, Zhang W, Shao C, Xu P, Shi CH, et al. Genistein sensitizes bladder cancer cells to HCPT treatment in vitro and in vivo via ATM/NF-κB/IKK pathway-induced apoptosis. PLoS One. 2013;8(1):e50175.
  • Liu D, Yan L, Wang L, Tai W, Wang W, Yang C. Genistein enhances the effect of cisplatin on the inhibition of non‑small cell lung cancer A549 cell growth in vitro and in vivo. Oncol Lett. 2014;8(6):2806–10.
  • Yuan L, Wang J, Xiao H, Xiao C, Wang Y, Liu X. Isoorientin induces apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cancer cells. Toxicol Appl Pharmacol. 2012;265(1):83–92. doi:10.1016/j.taap.2012.09.022.
  • Ye T, Su J, Huang C, Yu D, Dai S, Huang X, Chen B, Zhou M. Isoorientin induces apoptosis, decreases invasiveness, and downregulates VEGF secretion by activating AMPK signaling in pancreatic cancer cells. Onco Targets Ther. 2016;9:7481–92. doi:10.2147/OTT.S122653.
  • Zheng H, Zhang M, Luo H, Li H. Isoorientin alleviates UVB-induced skin injury by regulating mitochondrial ROS and cellular autophagy. Biochem Biophys Res Commun. 2019;514(4):1133–9. doi:10.1016/j.bbrc.2019.04.195.
  • Xu W-T, Shen G-N, Li T-Z, Zhang Y, Zhang T, Xue H, Zuo W-B, Li Y-N, Zhang D-J, Jin C-H, et al. Isoorientin induces the apoptosis and cell cycle arrest of A549 human lung cancer cells via the ROS‑regulated MAPK, STAT3 and NF‑κB signaling pathways. Int J Oncol. 2020;57(2):550–61. doi:10.3892/ijo.2020.5079.
  • Liu S-C, Huang C-S, Huang C-M, Hsieh M-S, Huang M-S, Fong I-H, Yeh C-T, Lin C-C. Isoorientin inhibits epithelial-to-mesenchymal properties and cancer stem-cell-like features in oral squamous cell carcinoma by blocking Wnt/β-catenin/STAT3 axis. Toxicol Appl Pharmacol. 2021;424:115581. 10.1016/j.taap.2021.115581
  • Ramos AA, Lima CF, Pereira M, Fernandes-Ferreira M, Pereira-Wilson C. Antigenotoxic effects of quercetin, rutin and ursolic acid on HepG2 cells: evaluation by the comet assay. Toxicol Lett. 2008;177(1):66–73. doi:10.1016/j.toxlet.2008.01.001.
  • Darband SG, Sadighparvar S, Yousefi B, Kaviani M, Ghaderi-Pakdel F, Mihanfar A, Rahimi Y, Mobaraki K, Majidinia M. Quercetin attenuated oxidative DNA damage through NRF2 signaling pathway in rats with DMH induced colon carcinogenesis. Life Sci. 2020;253:117584. doi:10.1016/j.lfs.2020.117584.
  • Mostafavi Pour Z, Ramezani F, Keshavarzi F, Samadi N. ‑The role of quercetin and vitamin C in Nrf2‑dependent oxidative stress production in breast cancer cells. Oncol Lett. 2017;13(3):1965–73. doi:10.3892/ol.2017.5619.
  • Abbasi A, Mostafavi-Pour Z, Amiri A, Keshavarzi F, Nejabat N, Ramezani F, Sardarian A, Zal F. Chemoprevention of prostate cancer cells by vitamin C plus quercetin: role of Nrf2 in inducing oxidative stress. Nutr Cancer. 2021;73(10):2003–13. doi:10.1080/01635581.2020.1819346.
  • Lee Y-J, Lee DM, Lee S-H. Nrf2 expression and apoptosis in quercetin-treated malignant mesothelioma cells. Mol Cells. 2015;38(5):416–25. doi:10.14348/molcells.2015.2268.
  • Sharmila G, Bhat FA, Arunkumar R, Elumalai P, Raja Singh P, Senthilkumar K, Arunakaran J. Chemopreventive effect of quercetin, a natural dietary flavonoid on prostate cancer in in vivo model. Clin Nutr. 2014;33(4):718–26. 10.1016/j.clnu.2013.08.011
  • Zhaorigetu, Farrag IM, Belal A, Badawi MHA, Abdelhady AA, Galala FMAA, El-Sharkawy A, El-Dahshan AA, Mehany, ABM. Antiproliferative, apoptotic effects and suppression of oxidative stress of quercetin against induced toxicity in lung cancer cells of rats: in vitro and in vivo study. J Cancer. 2021;12(17):5249–59. 10.7150/jca.52088
  • Kang KA, Piao MJ, Hyun YJ, Zhen AX, Cho SJ, Ahn MJ, Yi JM, Hyun JW. Luteolin promotes apoptotic cell death via upregulation of Nrf2 expression by DNA demethylase and the interaction of Nrf2 with p53 in human colon cancer cells. Exp Mol Med. 2019;51(4):1–14. doi:10.1038/s12276-019-0238-y.
  • Zuo Q, Wu R, Xiao X, Yang C, Yang Y, Wang C, Lin L, Kong A-N. The dietary flavone luteolin epigenetically activates the Nrf2 pathway and blocks cell transformation in human colorectal cancer HCT116 cells. J Cell Biochem. 2018;119(11):9573–82. doi:10.1002/jcb.27275.
  • Sabzichi M, Hamishehkar H, Ramezani F, Sharifi S, Tabasinezhad M, Pirouzpanah M, Ghanbari P, Samadi N. Luteolin-loaded phytosomes sensitize human breast carcinoma MDA-MB 231 cells to doxorubicin by suppressing Nrf2 mediated signalling. Asian Pac J Cancer Prev. 2014;15(13):5311–6. doi:10.7314/apjcp.2014.15.13.5311.
  • Iida K, Naiki T, Naiki-Ito A, Suzuki S, Kato H, Nozaki S, Nagai T, Etani T, Nagayasu Y, Ando R, et al. Luteolin suppresses bladder cancer growth via regulation of mechanistic target of rapamycin pathway. Cancer Sci. 2020;111(4):1165–79. 10.1111/cas.14334
  • Feng J, Zheng T, Hou Z, Lv C, Xue A, Han T, Han B, Sun X, Wei Y. Luteolin, an aryl hydrocarbon receptor ligand, suppresses tumor metastasis in vitro and in vivo. Oncol Rep. 2020;44(5):2231–40. 10.3892/or.2020.7781
  • Yao X, Jiang W, Yu D, Yan Z. Luteolin inhibits proliferation and induces apoptosis of human melanoma cells in vivo and in vitro by suppressing MMP-2 and MMP-9 through the PI3K/AKT pathway. Food Funct. 2019;10(2):703–12. 10.1039/c8fo02013b
  • Johnson JL, Dia VP, Wallig M, De Mejia EG. Luteolin and gemcitabine protect against pancreatic cancer in an orthotopic mouse model. Pancreas. 2015;44(1):144–51. 10.1097/MPA.0000000000000215
  • Qin T, Zhao J, Liu X, Li L, Zhang X, Shi X, Ke Y, Liu W, Huo J, Dong Y, et al. Luteolin combined with low‐dose paclitaxel synergistically inhibits epithelial–mesenchymal transition and induces cell apoptosis on esophageal carcinoma in vitro and in vivo. Phytother Res. 2021;35(11):6228–40. 10.1002/ptr.7267
  • Zhao J, Li L, Wang Z, Li L, He M, Han S, Dong Y, Liu X, Zhao W, Ke Y, et al. Luteolin attenuates cancer cell stemness in PTX-resistant oesophageal cancer cells through mediating SOX2 protein stability. Pharmacol Res. 2021;174:105939. 10.1016/j.phrs.2021.105939
  • Nafees S, Mehdi SH, Zafaryab M, Zeya B, Sarwar T, Rizvi MA. Synergistic interaction of rutin and silibinin on human colon cancer cell line. Arch Med Res. 2018;49(4):226–34. doi:10.1016/j.arcmed.2018.09.008.
  • Xie X, Feng J, Kang Z, Zhang S, Zhang L, Zhang Y, et al. Taxifolin protects RPE cells against oxidative stress-induced apoptosis. Mol Vis. 2017;23:520.
  • Li Q, Ren L, Zhang Y, Gu Z, Tan Q, Zhang T, et al. P38 signal transduction pathway has more cofactors on apoptosis of SGC-7901 gastric cancer cells induced by combination of rutin and oxaliplatin. BioMed Res Int. 2019;2019:6407210. doi:10.1155/2019/6407210.
  • Gao Y, Liu Z, Zhang X, He J, Pan Y, Hao F, Xie L, Li Q, Qiu X, Wang E, et al. Inhibition of cytoplasmic GSK-3β increases cisplatin resistance through activation of Wnt/β-catenin signaling in A549/DDP cells. Cancer Lett. 2013;336(1):231–9. doi:10.1016/j.canlet.2013.05.005.
  • Satari A, Amini SA, Raeisi E, Lemoigne Y, Heidarian E. Synergetic impact of combined 5-fluorouracil and rutin on apoptosis in pc3 cancer cells through the modulation of p53 gene expression. Adv Pharm Bull. 2019;9(3):462–9. doi:10.15171/apb.2019.055.
  • Elsayed HE, Ebrahim HY, Mohyeldin MM, Siddique AB, Kamal AM, Haggag EG, El Sayed KA. Rutin as a novel c-Met inhibitory lead for the control of triple negative breast malignancies. Nutr Cancer. 2017;69(8):1256–71. doi:10.1080/01635581.2017.1367936.
  • Zhang P, Sun S, Li N, Ho ASW, Kiang KMY, Zhang X, Cheng YS, Poon MW, Lee D, Pu JKS, et al. Rutin increases the cytotoxicity of temozolomide in glioblastoma via autophagy inhibition. J Neurooncol. 2017;132(3):393–400. doi:10.1007/s11060-017-2387-y.
  • Park MH, Kim S, Song Y-r, Kim S, Kim H-J, Na HS, et al. Rutin induces autophagy in cancer cells. Int J Oral Biol. 2016;41(1):45–51. doi:10.11620/IJOB.2016.41.1.045.
  • Imani A, Maleki N, Bohlouli S, Kouhsoltani M, Sharifi S, Maleki Dizaj S. Molecular mechanisms of anticancer effect of rutin. Phytother Res. 2021;35(5):2500–13.
  • Farha AK, Gan R-Y, Li H-B, Wu D-T, Atanasov AG, Gul K, Zhang J-R, Yang Q-Q, Corke H. The anticancer potential of the dietary polyphenol rutin: current status, challenges, and perspectives. Crit Rev Food Sci Nutr. 2022;62(3):832–59.
  • Ko JH, Sethi G, Um JY, Shanmugam MK, Arfuso F, Kumar AP, et al. The role of resveratrol in cancer therapy. Int J Mol Sci. 2017;18(12):2589. doi:10.3390/ijms18122589.
  • Wang F, Wang L, Qu C, Chen L, Geng Y, Cheng C, Yu S, Wang D, Yang L, Meng Z, et al. Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling. BMC Cancer. 2021;21(1):396. doi:10.1186/s12885-021-08158-z.
  • Kashafi E, Moradzadeh M, Mohamadkhani A, Erfanian S. Kaempferol increases apoptosis in human cervical cancer HeLa cells via PI3K/AKT and telomerase pathways. Biomed Pharmacother. 2017;89:573–7.
  • Li Q, Wei L, Lin S, Chen Y, Lin J, Peng J. Synergistic effect of kaempferol and 5‑fluorouracil on the growth of colorectal cancer cells by regulating the PI3K/Akt signaling pathway. Mol Med Rep. 2019;20(1):728–34.
  • Song H, Bao J, Wei Y, Chen Y, Mao X, Li J, Yang Z, Xue Y. Kaempferol inhibits gastric cancer tumor growth: an in vitro and in vivo study. Oncol Rep. 2015;33(2):868–74. doi:10.3892/or.2014.3662.
  • Fouzder C, Mukhuty A, Kundu R. Kaempferol inhibits Nrf2 signalling pathway via downregulation of Nrf2 mRNA and induces apoptosis in NSCLC cells. Arch Biochem Biophys. 2021;697:108700. doi:10.1016/j.abb.2020.108700.
  • Luo H, Rankin GO, Juliano N, Jiang B-H, Chen YC. Kaempferol inhibits VEGF expression and in vitro angiogenesis through a novel ERK-NFκB-cMyc-p21 pathway. Food Chem. 2012;130(2):321–8.
  • Kuo W-T, Tsai Y-C, Wu H-C, Ho Y-J, Chen Y-S, Yao C-H, et al. Radiosensitization of non-small cell lung cancer by kaempferol. Oncol Rep. 2015;34(5):2351–6.
  • Kim S-H, Hwang K-A, Choi K-C. Treatment with kaempferol suppresses breast cancer cell growth caused by estrogen and triclosan in cellular and xenograft breast cancer models. J Nutr Biochem. 2016;28:70–82.
  • Li C, Zhao Y, Yang D, Yu Y, Guo H, Zhao Z, Zhang B, Yin X. Inhibitory effects of kaempferol on the invasion of human breast carcinoma cells by downregulating the expression and activity of matrix metalloproteinase-9. Biochem Cell Biol. 2015;93(1):16–27.
  • Yao J, Zhang B, Ge C, Peng S, Fang J. Xanthohumol, a polyphenol chalcone present in hops, activating Nrf2 enzymes to confer protection against oxidative damage in PC12 cells. J Agric Food Chem. 2015;63(5):1521–31. doi:10.1021/jf505075n.
  • Lv H, Liu Q, Wen Z, Feng H, Deng X, Ci X. Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis. Redox Biol. 2017;12:311–24. doi:10.1016/j.redox.2017.03.001.
  • Liu X, Song Z, Bai J, Nauwynck H, Zhao Y, Jiang P. Xanthohumol inhibits PRRSV proliferation and alleviates oxidative stress induced by PRRSV via the Nrf2–HMOX1 axis. Vet Res. 2019;50(1):61. doi:10.1186/s13567-019-0679-2.
  • Li F, Yao Y, Huang H, Hao H, Ying M. Xanthohumol attenuates cisplatin-induced nephrotoxicity through inhibiting NF-κB and activating Nrf2 signaling pathways. Int Immunopharmacol. 2018;61:277–82. doi:10.1016/j.intimp.2018.05.017.
  • Bellezza I, Mierla AL, Minelli A. Nrf2 and NF-κB and their concerted modulation in cancer pathogenesis and progression. Cancers. 2010;2(2):483–97. 10.3390/cancers2020483
  • Zhou Y, Jiang Z, Lu H, Xu Z, Tong R, Shi J, Jia G. Recent advances of natural polyphenols activators for Keap1‐Nrf2 signaling pathway. Chem Biodivers. 2019;16(11):e1900400. doi:10.1002/cbdv.201900400.
  • Vakana E, Platanias LC. AMPK in BCR-ABL expressing leukemias. Regulatory effects and therapeutic implications. Oncotarget. 2011;2(12):1322.
  • Gao X, Deeb D, Liu Y, Gautam S, Dulchavsky SA, Gautam SC. Immunomodulatory activity of xanthohumol: inhibition of T cell proliferation, cell-mediated cytotoxicity and Th1 cytokine production through suppression of NF-κB. Immunopharmacol Immunotoxicol. 2009;31(3):477–84. doi:10.1080/08923970902798132.
  • Lee I-S, Lim J, Gal J, Kang JC, Kim HJ, Kang BY, Choi HJ. Anti-inflammatory activity of xanthohumol involves heme oxygenase-1 induction via NRF2-ARE signaling in microglial BV2 cells. Neurochem Int. 2011;58(2):153–60. doi:10.1016/j.neuint.2010.11.008.
  • Zajc I, Filipič M, Lah T. Xanthohumol induces different cytotoxicity and apoptotic pathways in malignant and normal astrocytes. Phytother Res. 2012;26(11):1709–13. doi:10.1002/ptr.4636.
  • Lee SH, Kim HJ, Lee JS, Lee I-S, Kang BY. Inhibition of topoisomerase I activity and efflux drug transporters’ expression by xanthohumol from hops. Arch Pharm Res. 2007;30(11):1435–9. doi:10.1007/BF02977368.
  • Aloqbi A, Omar U, Yousr M, Grace M, Lila MA, Howell N. Antioxidant activity of pomegranate juice and punicalagin. Nat Sci. 2016;8(06):235. doi:10.4236/ns.2016.86028.
  • Lin C-C, Hsu Y-F, Lin T-C. Effects of punicalagin and punicalin on carrageenan-induced inflammation in rats. Am J Chin Med. 1999;27(3–4):371–6. doi:10.1142/S0192415X99000422.
  • Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. Supplementation with hydroxytyrosol and punicalagin improves early atherosclerosis markers involved in the asymptomatic phase of atherosclerosis in the adult population: a randomized, placebo-controlled, crossover trial. Nutrients. 2019;11(3):640. 10.3390/nu11030640
  • Xu Y, Shi C, Wu Q, Zheng Z, Liu P, Li G, Peng X, Xia X. Antimicrobial activity of punicalagin against Staphylococcus aureus and its effect on biofilm formation. Foodborne Pathog Dis. 2017;14(5):282–7. doi:10.1089/fpd.2016.2226.
  • Li G, Yan C, Xu Y, Feng Y, Wu Q, Lv X, Yang B, Wang X, Xia X. Punicalagin inhibits Salmonella virulence factors and has anti-quorum-sensing potential. Appl Environ Microbiol. 2014;80(19):6204–11. doi:10.1128/AEM.01458-14.
  • Aqil F, Munagala R, Vadhanam MV, Kausar H, Jeyabalan J, Schultz DJ, Gupta RC. Anti-proliferative activity and protection against oxidative DNA damage by punicalagin isolated from pomegranate husk. Food Res Int. 2012;49(1):345–53. doi:10.1016/j.foodres.2012.07.059.
  • Xu X, Li H, Hou X, Li D, He S, Wan C, et al. Punicalagin induces Nrf2/HO-1 expression via upregulation of PI3K/AKT pathway and inhibits LPS-induced oxidative stress in RAW264. 7 macrophages. Mediat Inflamm. 2015;2015:380218. doi:10.1155/2015/380218.
  • Xu L, He S, Yin P, Li D, Mei C, Yu X, Shi Y, Jiang L, Liu F. Punicalagin induces Nrf2 translocation and HO-1 expression via PI3K/Akt, protecting rat intestinal epithelial cells from oxidative stress. Int J Hyperthermia. 2016;32(5):465–73. doi:10.3109/02656736.2016.1155762.
  • Zahin M, Ahmad I, Gupta RC, Aqil F. Punicalagin and ellagic acid demonstrate antimutagenic activity and inhibition of benzo [a] pyrene induced DNA adducts. Biomed Res Int. 2014;2014:467465. doi:10.1155/2014/467465.
  • Wardyn JD, Ponsford AH, Sanderson CM. Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways. Biochem Soc Trans. 2015;43(4):621–6. doi:10.1042/BST20150014.
  • Xu X, Yin P, Wan C, Chong X, Liu M, Cheng P, et al. Punicalagin inhibits inflammation in LPS-induced RAW264. 7 macrophages via the suppression of TLR4-mediated MAPKs and NF-κB activation. Inflammation. 2014;37(3):956–65.
  • Rubiolo JA, Mithieux G, Vega FV. Resveratrol protects primary rat hepatocytes against oxidative stress damage:: activation of the Nrf2 transcription factor and augmented activities of antioxidant enzymes. Eur J Pharmacol. 2008;591(1–3):66–72. doi:10.1016/j.ejphar.2008.06.067.
  • García-García J, Micol V, de Godos A, Gómez-Fernández JC. The cancer chemopreventive agent resveratrol is incorporated into model membranes and inhibits protein kinase C α activity. Arch Biochem Biophys. 1999;372(2):382–8. doi:10.1006/abbi.1999.1507.
  • Zhuang Y, Wu H, Wang X, He J, He S, Yin Y. Resveratrol attenuates oxidative stress-induced intestinal barrier injury through PI3K/Akt-mediated Nrf2 signaling pathway. Oxid Med Cell Longev. 2019;2019:7591840. doi:10.1155/2019/7591840.
  • Hsieh T-c, Lu X, Wang Z, Wu JM. Induction of quinone reductase NQO1 by resveratrol in human K562 cells involves the antioxidant response element ARE and is accompanied by nuclear translocation of transcription factor Nrf2. Med Chem. 2006;2(3):275–85. doi:10.2174/157340606776930709.
  • Lu F, Zahid M, Wang C, Saeed M, Cavalieri EL, Rogan EG. Resveratrol prevents estrogen-DNA adduct formation and neoplastic transformation in MCF-10F cells. Cancer Prev Res (Phila). 2008;1(2):135–45. doi:10.1158/1940-6207.CAPR-08-0037.
  • Zhang Y, Wang G, Wang T, Cao W, Zhang L, Chen X. Nrf2–Keap1 pathway–mediated effects of resveratrol on oxidative stress and apoptosis in hydrogen peroxide–treated rheumatoid arthritis fibroblast‐like synoviocytes. Ann N Y Acad Sci. 2019;1457(1):166–78. doi:10.1111/nyas.14196.
  • Roy P, Madan E, Kalra N, Nigam N, George J, Ray RS, Hans RK, Prasad S, Shukla Y. Resveratrol enhances ultraviolet B-induced cell death through nuclear factor-κB pathway in human epidermoid carcinoma A431 cells. Biochem Biophys Res Commun. 2009;384(2):215–20. doi:10.1016/j.bbrc.2009.04.100.
  • Chang J, Zhang Y, Li Y, Lu K, Shen Y, Guo Y, Qi Q, Wang M, Zhang S. NrF2/ARE and NF-κB pathway regulation may be the mechanism for lutein inhibition of human breast cancer cell. Future Oncol. 2018;14(8):719–26. doi:10.2217/fon-2017-0584.
  • Wu Y, Zhou BP. Inflammation: a driving force speeds cancer metastasis. Cell Cycle. 2009;8(20):3267–73. doi:10.4161/cc.8.20.9699.
  • Berman AY, Motechin RA, Wiesenfeld MY, Holz MK. The therapeutic potential of resveratrol: a review of clinical trials. npj Precis Oncol. 2017;1(1):1–9.
  • Tan KH, Nishida R. Methyl eugenol: its occurrence, distribution, and role in nature, especially in relation to insect behavior and pollination. J Insect Sci. 2012;12(1):56. doi:10.1673/031.012.5601.
  • Choi YK, Cho G-S, Hwang S, Kim BW, Lim JH, Lee J-C, Kim HC, Kim W-K, Kim YS. Methyleugenol reduces cerebral ischemic injury by suppression of oxidative injury and inflammation. Free Radic Res. 2010;44(8):925–35. doi:10.3109/10715762.2010.490837.
  • Shin B-K, Lee E-H, Kim H-M. Suppression ofL-histidine decarboxylase mRNA expression by methyleugenol. Biochem Biophys Res Commun. 1997;232(1):188–91. doi:10.1006/bbrc.1997.6260.
  • Zhou J, Ma X, Cui Y, Song Y, Yao L, Liu Y, Li S. Methyleugenol protects against t-BHP-triggered oxidative injury by induction of Nrf2 dependent on AMPK/GSK3β and ERK activation. J Pharmacol Sci. 2017;135(2):55–63. doi:10.1016/j.jphs.2017.09.003.
  • Ma L, Liu J, Lin Q, Gu Y, Yu W. Eugenol protects cells against oxidative stress via Nrf2. Exp Ther Med. 2021;21(2):1. doi:10.3892/etm.2020.9539.
  • Chen H, Fu J, Chen H, Hu Y, Soroka DN, Prigge JR, Schmidt EE, Yan F, Major MB, Chen X, et al. Ginger compound [6]-shogaol and its cysteine-conjugated metabolite (M2) activate Nrf2 in colon epithelial cells in vitro and in vivo. Chem Res Toxicol. 2014;27(9):1575–85. doi:10.1021/tx500211x.
  • Kim J-K, Jang H-D. 6-shogaol attenuates H2O2-induced oxidative stress via upregulation of Nrf2-mediated γ-glutamylcysteine synthetase and heme oxygenase expression in HepG2 cells. Food Sci Biotechnol. 2016;25(1):319–27. doi:10.1007/s10068-016-0045-3.
  • Hur J, Lee Y, Lee CJ, Park H-Y, Choi SY. 6-shogaol suppresses oxidative damage in L6 muscle cells. Appl Biol Chem. 2020;63(1):1–6. doi:10.1186/s13765-020-00544-8.
  • Peng S, Yao J, Liu Y, Duan D, Zhang X, Fang J. Activation of Nrf2 target enzymes conferring protection against oxidative stress in PC12 cells by ginger principal constituent 6-shogaol. Food Funct. 2015;6(8):2813–23. doi:10.1039/c5fo00214a.
  • Gan F-F, Ling H, Ang X, Reddy SA, Lee SS-H, Yang H, Tan S-H, Hayes JD, Chui W-K, Chew E-H, et al. A novel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-κB and Nrf2-Keap1 signaling pathways. Toxicol Appl Pharmacol. 2013;272(3):852–62. doi:10.1016/j.taap.2013.07.011.
  • Kim MO, Lee M-H, Oi N, Kim S-H, Bae KB, Huang Z, Kim DJ, Reddy K, Lee S-Y, Park SJ, et al. [6]-Shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2. Carcinogenesis. 2014;35(3):683–91. doi:10.1093/carcin/bgt365.
  • Chen F, Tang Y, Sun Y, Veeraraghavan VP, Mohan SK, Cui C. 6-shogaol, a active constiuents of ginger prevents UVB radiation mediated inflammation and oxidative stress through modulating NrF2 signaling in human epidermal keratinocytes (HaCaT cells). J Photochem Photobiol B. 2019;197:111518. doi:10.1016/j.jphotobiol.2019.111518.
  • Bischoff-Kont I, Fürst R. Benefits of ginger and its constituent 6-shogaol in inhibiting inflammatory processes. Pharmaceuticals (Basel). 2021;14(6):571. doi:10.3390/ph14060571.
  • Du Y-T, Zheng Y-L, Ji Y, Dai F, Hu Y-J, Zhou B. Applying an electrophilicity-based strategy to develop a novel nrf2 activator inspired from dietary [6]-shogaol. J Agric Food Chem. 2018;66(30):7983–94. doi:10.1021/acs.jafc.8b02442.
  • Yun N, Kang JW, Lee SM. Protective effects of chlorogenic acid against ischemia/reperfusion injury in rat liver: molecular evidence of its antioxidant and anti-inflammatory properties. J Nutr Biochem. 2012;23(10):1249–55. doi:10.1016/j.jnutbio.2011.06.018.
  • Liang N, Dupuis JH, Yada RY, Kitts DD. Chlorogenic acid isomers directly interact with Keap 1-Nrf2 signaling in Caco-2 cells. Mol Cell Biochem. 2019;457(1–2):105–18. doi:10.1007/s11010-019-03516-9.
  • Shi A, Shi H, Wang Y, Liu X, Cheng Y, Li H, Zhao H, Wang S, Dong L. Activation of Nrf2 pathway and inhibition of NLRP3 inflammasome activation contribute to the protective effect of chlorogenic acid on acute liver injury. Int Immunopharmacol. 2018;54:125–30. doi:10.1016/j.intimp.2017.11.007.
  • Bao L, Li J, Zha D, Zhang L, Gao P, Yao T, Wu X. Chlorogenic acid prevents diabetic nephropathy by inhibiting oxidative stress and inflammation through modulation of the Nrf2/HO-1 and NF-ĸB pathways. Int Immunopharmacol. 2018;54:245–53. doi:10.1016/j.intimp.2017.11.021.
  • Zhao X-L, Yu L, Zhang S-D, Ping K, Ni H-Y, Qin X-Y, Zhao C-J, Wang W, Efferth T, Fu Y-J, et al. Cryptochlorogenic acid attenuates LPS-induced inflammatory response and oxidative stress via upregulation of the Nrf2/HO-1 signaling pathway in RAW 264.7 macrophages. Int Immunopharmacol. 2020;83:106436. doi:10.1016/j.intimp.2020.106436.
  • Bender O, Atalay A. Polyphenol chlorogenic acid, antioxidant profile, and breast cancer. In: Preedy VR, Patel VB, editors. Cancer. Academic Press; 2021. p. 311–21. doi: 10.1016/B978-0-12-819547-5.00028-6.
  • Reczek CR, Chandel NS. The two faces of reactive oxygen species in cancer. Annu Rev Cancer Biol. 2017;1:79–98. doi:10.1146/annurev-cancerbio-041916-065808.
  • Hayakawa S, Ohishi T, Miyoshi N, Oishi Y, Nakamura Y, Isemura M. Anti-cancer effects of green tea epigallocatchin-3-gallate and coffee chlorogenic acid. Molecules. 2020;25(19):4553. doi:10.3390/molecules25194553.
  • Park JJ, Hwang SJ, Park J-H, Lee H-J. Chlorogenic acid inhibits hypoxia-induced angiogenesis via down-regulation of the HIF-1α/AKT pathway. Cell Oncol. 2015;38(2):111–8.
  • Lampiasi N, Montana G. An in vitro inflammation model to study the Nrf2 and NF-κB crosstalk in presence of ferulic acid as modulator. Immunobiology. 2018;223(4–5):349–55. doi:10.1016/j.imbio.2017.10.046.
  • Chaudhary A, Jaswal VS, Choudhary S, Sonika, Sharma A, Beniwal V, Tuli HS, Sharma S. Ferulic acid: a promising therapeutic phytochemical and recent patents advances. Recent Pat Inflamm Allergy Drug Discov. 2019;13(2):115–23. doi:10.2174/1872213X13666190621125048.
  • Mahmoud AM, Hussein OE, Hozayen WG, Bin-Jumah M, Abd El-Twab SM. Ferulic acid prevents oxidative stress, inflammation, and liver injury via upregulation of Nrf2/HO-1 signaling in methotrexate-induced rats. Environ Sci Pollut Res Int. 2020;27(8):7910–21. doi:10.1007/s11356-019-07532-6.
  • Yu CL, Zhao XM, Niu YC. Ferulic acid protects against lead acetate-induced inhibition of neurite outgrowth by upregulating HO-1 in PC12 cells: involvement of ERK1/2-Nrf2 pathway. Mol Neurobiol. 2016;53(9):6489–500. doi:10.1007/s12035-015-9555-x.
  • Ma ZC, Hong Q, Wang YG, Liang QD, Tan HL, Xiao CR, Tang XL, Shao S, Zhou SS, Gao Y, et al. Ferulic acid induces heme oxygenase-1 via activation of ERK and Nrf2. Drug Discov Ther. 2011;5(6):299–305. doi:10.5582/ddt.2011.v5.6.299.
  • Das U, Manna K, Khan A, Sinha M, Biswas S, Sengupta A, Chakraborty A, Dey S. Ferulic acid (FA) abrogates γ-radiation induced oxidative stress and DNA damage by up-regulating nuclear translocation of Nrf2 and activation of NHEJ pathway. Free Radic Res. 2017;51(1):47–63. doi:10.1080/10715762.2016.1267345.
  • Olivier S, Robe P, Bours V. Can NF-kappaB be a target for novel and efficient anti-cancer agents? Biochem Pharmacol. 2006;72(9):1054–68. doi:10.1016/j.bcp.2006.07.023.
  • Lampiasi N, Montana G. The molecular events behind ferulic acid mediated modulation of IL-6 expression in LPS-activated Raw 264.7 cells. Immunobiology. 2016;221(3):486–93. doi:10.1016/j.imbio.2015.11.001.
  • Choi YE, Park E. Ferulic acid in combination with PARP inhibitor sensitizes breast cancer cells as chemotherapeutic strategy. Biochem Biophys Res Commun. 2015;458(3):520–4. doi:10.1016/j.bbrc.2015.01.147.
  • Kovacs K, Vaczy A, Fekete K, Kovari P, Atlasz T, Reglodi D, Gabriel R, Gallyas F, Sumegi B. PARP inhibitor protects against chronic hypoxia/reoxygenation-induced retinal injury by regulation of MAPKs, HIF1α, Nrf2, and NFκB. Invest Ophthalmol Vis Sci. 2019;60(5):1478–90. doi:10.1167/iovs.18-25936.
  • Serreli G, Naitza MR, Zodio S, Leoni VP, Spada M, Melis MP, et al. Ferulic acid metabolites attenuate LPS-induced inflammatory response in enterocyte-like cells. Nutrients. 2021;13(9):3152. doi:10.3390/nu13093152.
  • Satoh T, Kosaka K, Itoh K, Kobayashi A, Yamamoto M, Shimojo Y, Kitajima C, Cui J, Kamins J, Okamoto S-i, et al. Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1. J Neurochem. 2008;104(4):1116–31. doi:10.1111/j.1471-4159.2007.05039.x.
  • de Oliveira MR, Ferreira GC, Schuck PF, Dal Bosco SM. Role for the PI3K/Akt/Nrf2 signaling pathway in the protective effects of carnosic acid against methylglyoxal-induced neurotoxicity in SH-SY5Y neuroblastoma cells. Chem Biol Interact. 2015;242:396–406. doi:10.1016/j.cbi.2015.11.003.
  • Xie Z, Zhong L, Wu Y, Wan X, Yang H, Xu X, Li P. Carnosic acid improves diabetic nephropathy by activating Nrf2/ARE and inhibition of NF-κB pathway. Phytomedicine. 2018;47:161–73. doi:10.1016/j.phymed.2018.04.031.
  • Lin Y, Bai L, Chen W, Xu S. The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opin Ther Targets. 2010;14(1):45–55. doi:10.1517/14728220903431069.
  • Khan MA, Jain VK, Rizwanullah M, Ahmad J, Jain K. PI3K/AKT/mTOR pathway inhibitors in triple-negative breast cancer: a review on drug discovery and future challenges. Drug Discov Today 2019;24(11):2181–91. doi:10.1016/j.drudis.2019.09.001
  • Ghoneum A, Said N. PI3K-AKT-mTOR and NFκB pathways in ovarian cancer: implications for targeted therapeutics. Cancers (Basel). 2019;11(7):949. doi:10.3390/cancers11070949.
  • Yang N, Xia Z, Shao N, Li B, Xue L, Peng Y, Zhi F, Yang Y. Carnosic acid prevents dextran sulfate sodium-induced acute colitis associated with the regulation of the Keap1/Nrf2 pathway. Sci Rep. 2017;7(1):11036. doi:10.1038/s41598-017-11408-5.
  • Gong J, Xie J, Bedolla R, Rivas P, Chakravarthy D, Freeman JW, Reddick R, Kopetz S, Peterson A, Wang H, et al. Combined targeting of STAT3/NF-κB/COX-2/EP4 for effective management of pancreatic cancer. Clin Cancer Res. 2014;20(5):1259–73. doi:10.1158/1078-0432.Ccr-13-1664.
  • Gao Q, Liu H, Yao Y, Geng L, Zhang X, Jiang L, Shi B, Yang F. Carnosic acid induces autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells. J Appl Toxicol. 2015;35(5):485–92. doi:10.1002/jat.3049.
  • Einbond LS, Wu H-A, Kashiwazaki R, He K, Roller M, Su T, Wang X, Goldsberry S. Carnosic acid inhibits the growth of ER-negative human breast cancer cells and synergizes with curcumin. Fitoterapia. 2012;83(7):1160–8. doi:10.1016/j.fitote.2012.07.006.
  • Shi B, Wang LF, Meng WS, Chen L, Meng ZL. Carnosic acid and fisetin combination therapy enhances inhibition of lung cancer through apoptosis induction. Int J Oncol. 2017;50(6):2123–35. doi:10.3892/ijo.2017.3970.
  • Chen CC, Chen HL, Hsieh CW, Yang YL, Wung BS. Upregulation of NF-E2-related factor-2-dependent glutathione by carnosol provokes a cytoprotective response and enhances cell survival. Acta Pharmacol Sin. 2011;32(1):62–9. doi:10.1038/aps.2010.181.
  • Foresti R, Bucolo C, Platania CM, Drago F, Dubois-Randé JL, Motterlini R. Nrf2 activators modulate oxidative stress responses and bioenergetic profiles of human retinal epithelial cells cultured in normal or high glucose conditions. Pharmacol Res. 2015;99:296–307. doi:10.1016/j.phrs.2015.07.006.
  • Wu KC, McDonald PR, Liu J, Klaassen CD. Screening of natural compounds as activators of the keap1-nrf2 pathway. Planta Med. 2014;80(1):97–104. doi:10.1055/s-0033-1351097.
  • Martin D, Rojo AI, Salinas M, Diaz R, Gallardo G, Alam J, De Galarreta CMR, Cuadrado A. Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol. J Biol Chem. 2004;279(10):8919–29. doi:10.1074/jbc.M309660200.
  • Vergara D, Simeone P, Bettini S, Tinelli A, Valli L, Storelli C, Leo S, Santino A, Maffia M. Antitumor activity of the dietary diterpene carnosol against a panel of human cancer cell lines. Food Funct. 2014;5(6):1261–9. doi:10.1039/c4fo00023d.
  • Park K-W, Kundu J, Chae I-G, Kim D-H, Yu M-H, Kundu JK, Chun K-S. Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells. Int J Oncol. 2014;44(4):1309–15. doi:10.3892/ijo.2014.2281.
  • Sanli T, Linher-Melville K, Tsakiridis T, Singh G. Sestrin2 modulates AMPK subunit expression and its response to ionizing radiation in breast cancer cells. PLoS One. 2012;7(2):e32035. doi:10.1371/journal.pone.0032035.
  • O’Neill EJ, Hartogh D, Azizi DJ, Tsiani K. E. Anticancer properties of carnosol: a summary of in vitro and in vivo evidence. Antioxidants. 2020;9(10):961.
  • Ding Y, Zhang B, Zhou K, Chen M, Wang M, Jia Y, Song Y, Li Y, Wen A. Dietary ellagic acid improves oxidant-induced endothelial dysfunction and atherosclerosis: role of Nrf2 activation. Int J Cardiol. 2014;175(3):508–14. doi:10.1016/j.ijcard.2014.06.045.
  • Ding X, Jian T, Wu Y, Zuo Y, Li J, Lv H, Ma L, Ren B, Zhao L, Li W, et al. Ellagic acid ameliorates oxidative stress and insulin resistance in high glucose-treated HepG2 cells via miR-223/keap1-Nrf2 pathway. Biomed Pharmacother. 2019;110:85–94. doi:10.1016/j.biopha.2018.11.018.
  • ALTamimi JZ, AlFaris NA, Aljabryn DH, Alagal RI, Alshammari GM, Aldera H, et al. Ellagic acid improved diabetes mellitus-induced testicular damage and sperm abnormalities by activation of Nrf2. Saudi J Biol Sci. 2021;28(8):4300–4310. doi:10.1016/j.sjbs.2021.04.005.
  • Yang H-L, Lin C-P, Vudhya Gowrisankar Y, Huang P-J, Chang W-L, Shrestha S, Hseu Y-C. The anti-melanogenic effects of ellagic acid through induction of autophagy in melanocytes and suppression of UVA-activated α-MSH pathways via Nrf2 activation in keratinocytes. Biochem Pharmacol. 2021;185:114454. doi:10.1016/j.bcp.2021.114454.
  • Edderkaoui M, Odinokova I, Ohno I, Gukovsky I, Go VLW, Pandol SJ, Gukovskaya AS. Ellagic acid induces apoptosis through inhibition of nuclear factor kappa B in pancreatic cancer cells. World J Gastroenterol. 2008;14(23):3672–80. doi:10.3748/wjg.14.3672.
  • Ebrahimi R, Sepand MR, Seyednejad SA, Omidi A, Akbariani M, Gholami M, Sabzevari O. Ellagic acid reduces methotrexate-induced apoptosis and mitochondrial dysfunction via up-regulating Nrf2 expression and inhibiting the IĸBα/NFĸB in rats. Daru. 2019;27(2):721–33. doi:10.1007/s40199-019-00309-9.
  • Ceci C, Tentori L, Atzori MG, Lacal PM, Bonanno E, Scimeca M, et al. Ellagic acid inhibits bladder cancer invasiveness and in vivo tumor growth. Nutrients. 2016;8(11):744.
  • Zhu H, Jin H, Pi J, Bai H, Yang F, Wu C, et al. Apigenin induced apoptosis in esophageal carcinoma cells by destruction membrane structures. Scanning. 2016;38(4):322–8.
  • Huang C-S, Lii C-K, Lin A-H, Yeh Y-W, Yao H-T, Li C-C, Wang T-S, Chen H-W. Protection by chrysin, apigenin, and luteolin against oxidative stress is mediated by the Nrf2-dependent up-regulation of heme oxygenase 1 and glutamate cysteine ligase in rat primary hepatocytes. Arch Toxicol. 2013;87(1):167–78. doi:10.1007/s00204-012-0913-4.
  • Paredes-Gonzalez X, Fuentes F, Jeffery S, Saw CL-L, Shu L, Su Z-Y, Kong A-NT. Induction of NRF2‐mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharm Drug Dispos. 2015;36(7):440–51. doi:10.1002/bdd.1956.
  • Zhang B, Wang J, Zhao G, Lin M, Lang Y, Zhang D, Feng D, Tu C. Apigenin protects human melanocytes against oxidative damage by activation of the Nrf2 pathway. Cell Stress Chaperones. 2020;25(2):277–85. doi:10.1007/s12192-020-01071-7.
  • Ozbey U, Attar R, Romero MA, Alhewairini SS, Afshar B, Sabitaliyevich UY, Hanna-Wakim L, Ozcelik B, Farooqi AA. Apigenin as an effective anticancer natural product: spotlight on TRAIL, WNT/β‐catenin, JAK‐STAT pathways, and microRNAs. J Cell Biochem. 2019;120(2):1060–7. doi:10.1002/jcb.27575.
  • Sharma A, Ghani A, Sak K, Tuli HS, Sharma AK, Setzer WN, Sharma S, Das AK. Probing into therapeutic anti-cancer potential of apigenin: recent trends and future directions. Recent Pat Inflamm Allergy Drug Discov. 2019;13(2):124–33. doi:10.2174/1872213X13666190816160240.
  • Javed Z, Sadia H, Iqbal MJ, Shamas S, Malik K, Ahmed R, et al. Apigenin role as cell-signaling pathways modulator: implications in cancer prevention and treatment. Cancer Cell Int. 2021;21(1):1–11. doi:10.1186/s12935-021-01888-x.
  • Soni RP, Katoch M, Kumar A, Ladohiya R, Verma P. Tea: production, composition, consumption and its potential as an antioxidant and antimicrobial agent. Int J Food Ferment Technol. 2015;5(2):95–106. doi:10.5958/2277-9396.2016.00002.7.
  • Jing X, Zhang J, Huang Z, Sheng Y, Ji L. The involvement of Nrf2 antioxidant signalling pathway in the protection of monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats by (+)-catechin hydrate. Free Radic Res. 2018;52(4):402–14. doi:10.1080/10715762.2018.1437914.
  • Fan F-Y, Sang L-X, Jiang M. Catechins and their therapeutic benefits to inflammatory bowel disease. Molecules. 2017;22(3):484.
  • Suganuma M, Saha A, Fujiki H. New cancer treatment strategy using combination of green tea catechins and anticancer drugs. Cancer Sci. 2011;102(2):317–23. doi:10.1111/j.1349-7006.2010.01805.x.
  • Cheng Y-T, Wu C-H, Ho C-Y, Yen G-C. Catechin protects against ketoprofen-induced oxidative damage of the gastric mucosa by up-regulating Nrf2 in vitro and in vivo. J Nutr Biochem. 2013;24(2):475–83. doi:10.1016/j.jnutbio.2012.01.010.
  • Shay J, Elbaz HA, Lee I, Zielske SP, Malek MH, Hüttemann M. Molecular mechanisms and therapeutic effects of (−)-epicatechin and other polyphenols in cancer, inflammation, diabetes, and neurodegeneration. Oxid Med Cell Longev. 2015;2015:181260. doi:10.1155/2015/181260.
  • Chiou Y-S, Huang Q, Ho C-T, Wang Y-J, Pan M-H. Directly interact with Keap1 and LPS is involved in the anti-inflammatory mechanisms of (-)-epicatechin-3-gallate in LPS-induced macrophages and endotoxemia. Free Radic Biol Med. 2016;94:1–16. doi:10.1016/j.freeradbiomed.2016.02.010.
  • Bahia PK, Rattray M, Williams RJ. Dietary flavonoid (−) epicatechin stimulates phosphatidylinositol 3‐kinase‐dependent anti‐oxidant response element activity and up‐regulates glutathione in cortical astrocytes. J Neurochem. 2008;106(5):2194–204.doi:10.1111/j.1471-4159.2008.05542.x.
  • Granado-Serrano AB, Martín MA, Haegeman G, Goya L, Bravo L, Ramos S. Epicatechin induces NF-κB, activator protein-1 (AP-1) and nuclear transcription factor erythroid 2p45-related factor-2 (Nrf2) via phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and extracellular regulated kinase (ERK) signalling in HepG2 cells. Br J Nutr. 2010;103(2):168–79. doi:10.1017/S0007114509991747.
  • Mayer IA, Arteaga CL. The PI3K/AKT pathway as a target for cancer treatment. Annu Rev Med. 2016;67:11–28. doi:10.1146/annurev-med-062913-051343.
  • Wu C, Hsu M, Hsieh C, Lin J, Lai P, Wung B. Upregulation of heme oxygenase-1 by Epigallocatechin-3-gallate via the phosphatidylinositol 3-kinase/Akt and ERK pathways. Life Sci. 2006;78(25):2889–97. doi:10.1016/j.lfs.2005.11.013.
  • Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22(2):153–83. doi:10.1210/edrv.22.2.0428.
  • Andreadi CK, Howells LM, Atherfold PA, Manson MM. Involvement of Nrf2, p38, B-Raf, and nuclear factor-κB, but not phosphatidylinositol 3-kinase, in induction of hemeoxygenase-1 by dietary polyphenols. Mol Pharmacol. 2006;69(3):1033–40. doi:10.1124/mol.105.018374.
  • Shimizu M, Shirakami Y, Moriwaki H. Targeting receptor tyrosine kinases for chemoprevention by green tea catechin, EGCG. Int J Mol Sci. 2008;9(6):1034–49. doi:10.3390/ijms9061034.
  • Han SG, Han S-S, Toborek M, Hennig B. EGCG protects endothelial cells against PCB 126-induced inflammation through inhibition of AhR and induction of Nrf2-regulated genes. Toxicol Appl Pharmacol. 2012;261(2):181–8. doi:10.1016/j.taap.2012.03.024.
  • Na H-K, Surh Y-J. Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction by the green tea polyphenol EGCG. Food Chem Toxicol. 2008;46(4):1271–8. doi:10.1016/j.fct.2007.10.006.
  • Chen C, Yu R, Owuor ED, Kong A-NT. Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death. Arch Pharm Res. 2000;23(6):605–12. doi:10.1007/BF02975249.
  • Hwang J-T, Ha J, Park I-J, Lee S-K, Baik HW, Kim YM, Park OJ. Apoptotic effect of EGCG in HT-29 colon cancer cells via AMPK signal pathway. Cancer Lett. 2007;247(1):115–21. doi:10.1016/j.canlet.2006.03.030.
  • Wada Y, Takata A, Ikemoto T, Morine Y, Imura S, Iwahashi S, Saito Y, Shimada M. The protective effect of epigallocatechin 3-gallate on mouse pancreatic islets via the Nrf2 pathway. Surg Today. 2019;49(6):536–45. doi:10.1007/s00595-019-1761-0.
  • Shankar S, Ganapathy S, Hingorani SR, Srivastava RK. EGCG inhibits growth, invasion, angiogenesis and metastasis of pancreatic cancer. Front Biosci. 2008;13(1):440–52. doi:10.2741/2691.
  • Zhang W, Zhang W, Sun L, Xiang L, Lai X, Li Q, et al. The effects and mechanisms of epigallocatechin-3-gallate on reversing multidrug resistance in cancer. Trends Food Sci Technol. 2019;93:221–33. doi:10.1016/j.tifs.2019.09.017.
  • Li M-J, Yin Y-C, Wang J, Jiang Y-F. Green tea compounds in breast cancer prevention and treatment. World J Clin Oncol. 2014;5(3):520–8. doi:10.5306/wjco.v5.i3.520.
  • Huang Y-J, Wang K-L, Chen H-Y, Chiang Y-F, Hsia S-M. Protective effects of epigallocatechin gallate (EGCG) on endometrial, breast, and ovarian cancers. Biomolecules. 2020;10(11):1481. doi:10.3390/biom10111481.
  • Higa S, Hirano T, Kotani M, Matsumoto M, Fujita A, Suemura M, Kawase I, Tanaka T. Fisetin, a flavonol, inhibits TH2-type cytokine production by activated human basophils. J Allergy Clin Immunol. 2003;111(6):1299–306. doi:10.1067/mai.2003.1456.
  • Zhang H, Zheng W, Feng X, Yang F, Qin H, Wu S, et al. Nrf2–ARE signaling acts as master pathway for the cellular antioxidant activity of fisetin. Molecules. 2019;24(4):708.
  • Li Y, Liu Y, Chen J, Hu J. Protective effect of Fisetin on the lipopolysaccharide-induced preeclampsia-like rats. Hyperten Pregnancy. 2022;2021:1–8. doi:10.1080/10641955.2021.2013874.
  • Ahmad S, Khan A, Ali W, Jo MH, Park J, Ikram M, et al. Fisetin rescues the mice brains against D-galactose-induced oxidative stress, neuroinflammation and memory impairment. Front Pharmacol. 2021;12:612078. doi:10.3389/fphar.2021.612078.
  • Lee SE, Jeong SI, Yang H, Park CS, Jin YH, Park YS. Fisetin induces Nrf2‐mediated HO‐1 expression through PKC‐δ and p38 in human umbilical vein endothelial cells. J Cell Biochem. 2011;112(9):2352–60. doi:10.1002/jcb.23158.
  • Yen J-H, Wu P-S, Chen S-F, Wu M-J. Fisetin protects PC12 cells from tunicamycin-mediated cell death via reactive oxygen species scavenging and modulation of Nrf2-driven gene expression, SIRT1 and MAPK signaling in PC12 cells. Int J Mol Sci. 2017;18(4):852. doi:10.3390/ijms18040852.
  • Sun Y, Liu W-Z, Liu T, Feng X, Yang N, Zhou H-F. Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res. 2015;35(6):600–4. doi:10.3109/10799893.2015.1030412.
  • Yang P-M, Tseng H-H, Peng C-W, Chen W-S, Chiu S-J. 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(2):469–78. doi:10.3892/ijo.2011.1203.
  • 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):2502–14. doi:10.1080/01635581.2020.1836241.
  • Hada Y, Uchida HA, Wada J. Fisetin attenuates lipopolysaccharide-induced inflammatory responses in macrophage. Biomed Res Int. 2021;2021:5570885. doi:10.1155/2021/5570885.
  • Molagoda IMN, Athapaththu A, Choi YH, Park C, Jin CY, Kang CH, et al. Fisetin inhibits NLRP3 inflammasome by suppressing TLR4/MD2-mediated mitochondrial ROS production. Antioxidants (Basel, Switzerland). 2021;10(8):1215. doi:10.3390/antiox10081215.
  • Chenxu G, Xianling D, Qin K, Linfeng H, Yan S, Mingxin X, Jun T, Minxuan X. Fisetin protects against high fat diet-induced nephropathy by inhibiting inflammation and oxidative stress via the blockage of iRhom2/NF-κB signaling. Int Immunopharmacol. 2021;92:107353. doi:10.1016/j.intimp.2020.107353.
  • Pu J-L, Huang Z-T, Luo Y-H, Mou T, Li T-T, Li Z-T, Wei X-F, Wu Z-J. Fisetin mitigates hepatic ischemia-reperfusion injury by regulating GSK3β/AMPK/NLRP3 inflammasome pathway. Hepatobiliary Pancreat Dis Int. 2021;20(4):352–60. doi:10.1016/j.hbpd.2021.04.013.
  • Sim H, Choo S, Kim J, Baek M-C, Bae J-S. Fisetin suppresses pulmonary inflammatory responses through heme oxygenase-1 mediated downregulation of inducible nitric oxide synthase. J Med Food. 2020;23(11):1163–8. doi:10.1089/jmf.2020.4755.
  • Peng H-L, Huang W-C, Cheng S-C, Liou C-J. Fisetin inhibits the generation of inflammatory mediators in interleukin-1β–induced human lung epithelial cells by suppressing the NF-κB and ERK1/2 pathways. Int Immunopharmacol. 2018;60:202–10. doi:10.1016/j.intimp.2018.05.004.
  • Bhat TA, Nambiar D, Pal A, Agarwal R, Singh RP. Fisetin inhibits various attributes of angiogenesis in vitro and in vivo—implications for angioprevention. Carcinogenesis. 2012;33(2):385–93.
  • Li L, Wang M, Yang H, Li Y, Huang X, Guo J, et al. Fisetin inhibits trypsin activity and suppresses the growth of colorectal cancer in vitro and in vivo. Nat Prod Commun. 2022;17(8). doi:10.1177/1934578X221115511.
  • Sarkar FH, Li Y. Mechanisms of cancer chemoprevention by soy isoflavone genistein. Cancer Metastasis Rev. 2002;21(3–4):265–80. doi:10.1023/a:1021210910821.
  • Zhang T, Wang F, Xu H-X, Yi L, Qin Y, Chang H, et al. Activation of nuclear factor erythroid 2-related factor 2 and PPARγ plays a role in the genistein-mediated attenuation of oxidative stress-induced endothelial cell injury. Br J Nutr. 2013;109(2):223–35.
  • Zhai X, Lin M, Zhang F, Hu Y, Xu X, Li Y, Liu K, Ma X, Tian X, Yao J, et al. Dietary flavonoid genistein induces Nrf2 and phase II detoxification gene expression via ERKs and PKC pathways and protects against oxidative stress in Caco‐2 cells. Mol Nutr Food Res. 2013;57(2):249–59. doi:10.1002/mnfr.201200536.
  • Xi Y-D, Yu H-L, Ding J, Ma W-W, Yuan L-H, Feng J-F, Xiao Y-X, Xiao R. Flavonoids protect cerebrovascular endothelial cells through Nrf2 and PI3K from β-amyloid peptide-induced oxidative damage. Curr Neurovasc Res. 2012;9(1):32–41. doi:10.2174/156720212799297092.
  • Noorolyai S, Shajari N, Baghbani E, Sadreddini S, Baradaran B. The relation between PI3K/AKT signalling pathway and cancer. Gene. 2019;698:120–8. 10.1016/j.gene.2019.02.076
  • Liu F-C, Wang C-C, Lu J-W, Lee C-H, Chen S-C, Ho Y-J, et al. Chondroprotective effects of genistein against osteoarthritis induced joint inflammation. Nutrients. 2019;11(5):1180.
  • Wang L, Li A, Liu Y, Zhan S, Zhong L, Du Y, Xu D, Wang W, Huang W. Genistein protects against acetaminophen-induced liver toxicity through augmentation of SIRT1 with induction of Nrf2 signalling. Biochem Biophys Res Commun. 2020;527(1):90–7. doi:10.1016/j.bbrc.2020.04.100.
  • Kim E-J, Um S-J. SIRT1: roles in aging and cancer. BMB Rep. 2008;41(11):751–6.
  • Zhang L, Li H, Gao M, Zhang T, Wu Z, Wang Z, Chong T. Genistein attenuates di‑(2‑ethylhexyl) phthalate-induced testicular injuries via activation of Nrf2/HO‑1 following prepubertal exposure. Int J Mol Med. 2018;41(3):1437–46. doi:10.3892/ijmm.2018.3371.
  • Gundogdu G, Dodurga Y, Elmas L, Tasci SY, Karaoglan ES. Investigation of the anticancer mechanism of isoorientin isolated from Eremurus spectabilis leaves via cell cycle pathways in HT-29 human colorectal adenocarcinoma cells. Eurasian J Med. 2018;50(3):168. doi:10.5152/eurasianjmed.2018.17403.
  • Ma L, Zhang B, Liu J, Qiao C, Liu Y, Li S, Lv H. Isoorientin exerts a protective effect against 6-OHDA-induced neurotoxicity by activating the AMPK/AKT/Nrf2 signalling pathway. Food Funct. 2020;11(12):10774–85. doi:10.1039/d0fo02165b.
  • Yuan L, Wang J, Wu W, Liu Q, Liu X. Effect of isoorientin on intracellular antioxidant defence mechanisms in hepatoma and liver cell lines. Biomed Pharmacother. 2016;81:356–62. doi:10.1016/j.biopha.2016.04.025.
  • Yuan L, Wang J, Xiao H, Wu W, Wang Y, Liu X. MAPK signaling pathways regulate mitochondrial-mediated apoptosis induced by isoorientin in human hepatoblastoma cancer cells. Food Chem Toxicol. 2013;53:62–8. doi:10.1016/j.fct.2012.11.048.
  • Anilkumar K, Reddy GV, Azad R, Yarla NS, Dharmapuri G, Srivastava A, et al. Evaluation of anti-inflammatory properties of isoorientin isolated from tubers of Pueraria tuberosa. Oxid Med Cell Longev. 2017;2017:5498054. doi:10.1155/2017/5498054.
  • Li Y, Zhao Y, Tan X, Liu J, Zhi Y, Yi L, Bai S, Du Q, Li QX, Dong Y, et al. Isoorientin inhibits inflammation in macrophages and endotoxemia mice by regulating glycogen synthase kinase 3β. Mediators Inflamm. 2020;2020:8704146–11. doi:10.1155/2020/8704146.
  • Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. 2008;585(2–3):325–37. doi:10.1016/j.ejphar.2008.03.008.
  • Tanigawa S, Fujii M, Hou D-X. Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med. 2007;42(11):1690–703. doi:10.1016/j.freeradbiomed.2007.02.017.
  • Granado-Serrano AB, Martín MA, Bravo L, Goya L, Ramos S. Quercetin modulates Nrf2 and glutathione-related defenses in HepG2 cells: involvement of p38. Chem Biol Interact. 2012;195(2):154–64. doi:10.1016/j.cbi.2011.12.005.
  • Liao W, Chen L, Ma X, Jiao R, Li X, Wang Y. Protective effects of kaempferol against reactive oxygen species-induced hemolysis and its antiproliferative activity on human cancer cells. Eur J Med Chem. 2016;114:24–32. doi:10.1016/j.ejmech.2016.02.045.
  • Weng C-J, Chen M-J, Yeh C-T, Yen G-C. Hepatoprotection of quercetin against oxidative stress by induction of metallothionein expression through activating MAPK and PI3K pathways and enhancing Nrf2 DNA-binding activity. N Biotechnol. 2011;28(6):767–77. doi:10.1016/j.nbt.2011.05.003.
  • Sun L, Xu G, Dong Y, Li M, Yang L, Lu W. Quercetin protects against lipopolysaccharide-induced intestinal oxidative stress in broiler chickens through activation of Nrf2 pathway. Molecules. 2020;25(5):1053. doi:10.3390/molecules25051053.
  • Ramyaa P, Krishnaswamy R, Padma VV. Quercetin modulates OTA-induced oxidative stress and redox signalling in HepG2 cells—up regulation of Nrf2 expression and down regulation of NF-κB and COX-2. Biochim Biophys Acta. 2014;1840(1):681–92. doi:10.1016/j.bbagen.2013.10.024.
  • Zhao X, Wang J, Deng Y, Liao L, Zhou M, Peng C, Li Y. Quercetin as a protective agent for liver diseases: a comprehensive descriptive review of the molecular mechanism. Phytother Res. 2021;35(9):4727–47. doi:10.1002/ptr.7104.
  • Liu C-M, Ma J-Q, Xie W-R, Liu S-S, Feng Z-J, Zheng G-H, Wang A-M. Quercetin protects mouse liver against nickel-induced DNA methylation and inflammation associated with the Nrf2/HO-1 and p38/STAT1/NF-κB pathway. Food Chem Toxicol. 2015;82:19–26. doi:10.1016/j.fct.2015.05.001.
  • Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD. Dual roles of Nrf2 in cancer. Pharmacol Res. 2008;58(5–6):262–70. doi:10.1016/j.phrs.2008.09.003.
  • Saw CLL, Guo Y, Yang AY, Paredes-Gonzalez X, Ramirez C, Pung D, Kong A-NT. The berry constituents quercetin, kaempferol, and pterostilbene synergistically attenuate reactive oxygen species: involvement of the Nrf2-ARE signaling pathway. Food Chem Toxicol. 2014;72:303–11. doi:10.1016/j.fct.2014.07.038.
  • Tang S-M, Deng X-T, Zhou J, Li Q-P, Ge X-X, Miao L. Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects. Biomed Pharmacother. 2020;121:109604. 10.1016/j.biopha.2019.109604
  • Lin Y, Shi R, Wang X, Shen HM. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets. 2008;8(7):634–46. doi:10.2174/156800908786241050.
  • Lin C-W, Wu M-J, Liu IY-C, Su J-D, Yen J-H. Neurotrophic and cytoprotective action of luteolin in PC12 cells through ERK-dependent induction of Nrf2-driven HO-1 expression. J Agric Food Chem. 2010;58(7):4477–86. doi:10.1021/jf904061x.
  • Yan Y, Jun C, Lu Y, Jiangmei S. Combination of metformin and luteolin synergistically protects carbon tetrachloride‐induced hepatotoxicity: mechanism involves antioxidant, anti‐inflammatory, antiapoptotic, and Nrf2/HO‐1 signaling pathway. Biofactors. 2019;45(4):598–606. 10.1002/biof.1521
  • Li L, Luo W, Qian Y, Zhu W, Qian J, Li J. Luteolin protects against diabetic cardiomyopathy by inhibiting NF-κB-mediated inflammation and activating the Nrf2-mediated antioxidant responses. Phytomedicine. 2019;59:152774.
  • Xiao C, Xia M-L, Wang J, Zhou X-R, Lou Y-Y, Tang L-H, et al. Luteolin attenuates cardiac ischemia/reperfusion injury in diabetic rats by modulating Nrf2 antioxidative function. Oxid Med Cell Longev. 2019;2019:2719252. doi:10.1155/2019/2719252.
  • Rajput SA, Shaukat A, Wu K, Rajput I, Dost R, Baloch M, et al. Luteolin alleviates aflatoxinB1-induced apoptosis and oxidative stress in the liver of mice through activation of Nrf2 signaling pathway. Antioxidants (Basel). 2021;10(8):1268. doi:10.3390/antiox10081268.
  • Yang H, Liu BF, Xie FJ, Yang WL, Cao N. Luteolin induces mitochondrial apoptosis in HT29 cells by inhibiting the Nrf2/ARE signaling pathway. Exp Ther Med. 2020;19(3):2179–2187. doi:10.3892/etm.2020.8464.
  • Wang X-J, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, Chen W, Yi X, Zheng W, Wondrak GT, et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis. 2008;29(6):1235–43. doi:10.1093/carcin/bgn095.
  • Chian S, Thapa R, Chi Z, Wang XJ, Tang X. Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo. Biochem Biophys Res Commun. 2014;447(4):602–8. doi:10.1016/j.bbrc.2014.04.039.
  • Tsai KJ, Tsai HY, Tsai CC, Chen TY, Hsieh TH, Chen CL, et al. Luteolin inhibits breast cancer stemness and enhances chemosensitivity through the Nrf2-mediated pathway. Molecules. 2021;26(21):6452. doi:10.3390/molecules26216452.
  • Chian S, Li Y-Y, Wang X-J, Tang X-W. Luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway. Asian Pac J Cancer Prev. 2014;15(6):2911–6. doi:10.7314/apjcp.2014.15.6.2911.
  • Nouri Z, Fakhri S, Nouri K, Wallace CE, Farzaei MH, Bishayee A. Targeting multiple signaling pathways in cancer: the rutin therapeutic approach. Cancers. 2020;12(8):2276. 10.3390/cancers12082276
  • Manna K, Khan A, Biswas S, Das U, Sengupta A, Dey S, et al. editors. Rutin reverses radiation-induced oxidative DNA damage and inflammation through the modulation of p38/Nf-Kb and Keap1/Nrf2 pathway. Proceedings of the fourteenth annual meeting of the Society for Free Radical Research-India and international conference on translational research in ionizing radiation, free radicals, antioxidants and functional food; 2016.
  • Kongara S, Karantza V. The interplay between autophagy and ROS in tumorigenesis. Front Oncol. 2012;2:171. doi:10.3389/fonc.2012.00171.
  • Domitrović R, Jakovac H, Vasiljev Marchesi V, Vladimir-Knežević S, Cvijanović O, Tadić Z, Romić Z, Rahelić D. Differential hepatoprotective mechanisms of rutin and quercetin in CCl 4-intoxicated BALB/cN mice. Acta Pharmacol Sin. 2012;33(10):1260–70. 10.1038/aps.2012.62
  • Fulda S. Autophagy in cancer therapy. Front Oncol. 2017;7:128. doi:10.3389/fonc.2017.00128.
  • Oluranti OI, Alabi BA, Michael OS, Ojo AO, Fatokun BP. Rutin prevents cardiac oxidative stress and inflammation induced by bisphenol A and dibutyl phthalate exposure via NRF-2/NF-κB pathway. Life Sci. 2021;284:119878. doi:10.1016/j.lfs.2021.119878.
  • Gęgotek A, Ambrożewicz E, Jastrząb A, Jarocka-Karpowicz I, Skrzydlewska E. Rutin and ascorbic acid cooperation in antioxidant and antiapoptotic effect on human skin keratinocytes and fibroblasts exposed to UVA and UVB radiation. Arch Dermatol Res. 2019;311(3):203–19. doi:10.1007/s00403-019-01898-w.
  • Hussein RM, Mohamed WR, Omar HA. A neuroprotective role of kaempferol against chlorpyrifos-induced oxidative stress and memory deficits in rats via GSK3β-Nrf2 signaling pathway. Pestic Biochem Physiol. 2018;152:29–37. doi:10.1016/j.pestbp.2018.08.008.
  • Alshehri AS. Kaempferol attenuates diabetic nephropathy in streptozotocin-induced diabetic rats by a hypoglycaemic effect and concomitant activation of the Nrf-2/Ho-1/antioxidants axis. Arch Physiol Biochem. 2021;1–14. doi:10.1080/13813455.2021.1890129.
  • Wang Z, Sun W, Sun X, Wang Y, Zhou M. Kaempferol ameliorates Cisplatin induced nephrotoxicity by modulating oxidative stress, inflammation and apoptosis via ERK and NF-κB pathways. AMB Express. 2020;10(1):1–11.
  • Kumar AN, Bevara GB, Kaja LK, Badana AK, Malla RR. Protective effect of 3-O-methyl quercetin and kaempferol from Semecarpus anacardium against H2O2 induced cytotoxicity in lung and liver cells. BMC Complement Altern Med. 2016;16(1):1–13. doi:10.1186/s12906-016-1354-z.
  • Kitakaze T, Makiyama A, Nakai R, Kimura Y, Ashida H. Kaempferol modulates TCDD-and t-BHQ-induced drug-metabolizing enzymes and luteolin enhances this effect. Food Funct. 2020;11(4):3668–80. doi:10.1039/c9fo02951f.
  • Yao H, Sun J, Wei J, Zhang X, Chen B, Lin Y. Kaempferol protects blood vessels from damage induced by oxidative stress and inflammation in association with the Nrf2/HO-1 signaling pathway. Front Pharmacol. 2020;11:1118. doi:10.3389/fphar.2020.01118.
  • Yang Y, Wang Y, Wang T, Jiang X. O26 Screening active components of Modified Xiaoyao Powder for chemoprevention in breast cancer cells: involvement of the NRF2/NQO1 signalling pathway. Biochem Pharmacol. 2017;139:117–8. doi:10.1016/j.bcp.2017.06.091.
  • El-Kott AF, Bin-Meferij MM, Eleawa SM, Alshehri MM. Kaempferol protects against cadmium chloride-induced memory loss and hippocampal apoptosis by increased intracellular glutathione stores and activation of PTEN/AMPK induced inhibition of Akt/mTOR signaling. Neurochem Res. 2020;45(2):295–309. doi:10.1007/s11064-019-02911-4.
  • Polivka J, Jr., Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 2014;142(2):164–75. doi:10.1016/j.pharmthera.2013.12.004.
  • Wang Y, Chen B, Wang Z, Zhang W, Hao K, Chen Y, et al. Marsdenia tenacissimae extraction (MTE) inhibits the proliferation and induces the apoptosis of human acute T cell leukemia cells through inactivating PI3K/AKT/mTOR signaling pathway via PTEN enhancement. Oncotarget. 2016;7(50):82851.
  • Cho HJ, Park JHY. Kaempferol induces cell cycle arrest in HT-29 human colon cancer cells. J Cancer Prev. 2013;18(3):257–63. doi:10.15430/jcp.2013.18.3.257.
  • Al Sabaani N. Kaempferol protects against hydrogen peroxide-induced retinal pigment epithelium cell inflammation and apoptosis by activation of SIRT1 and inhibition of PARP1. J Ocul Pharmacol Ther. 2020;36(7):563–77. doi:10.1089/jop.2019.0151.
  • Gao Y, Yin J, Rankin GO, Chen YC. Kaempferol induces G2/M cell cycle arrest via checkpoint kinase 2 and promotes apoptosis via death receptors in human ovarian carcinoma A2780/CP70 cells. Molecules. 2018;23(5):1095.
  • Kang G-l, Jing Z-x Kaempferol alleviates ox-LDL-mediated endothelial cell injury via regulating AMPK/Nrf2/HO-1 signaling pathway. Chin J Microbiol Immunol. 2018;34(4):525–30.
  • Du Y, Han J, Zhang H, Xu J, Jiang L, Ge W. Kaempferol prevents against Ang II-induced cardiac remodeling through attenuating Ang II-induced inflammation and oxidative stress. J Cardiovasc Pharmacol. 2019;74(4):326–35. doi:10.1097/fjc.0000000000000713.