Generic placeholder image

Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Mini-Review Article

Flavonoids Overcome Drug Resistance to Cancer Chemotherapy by Epigenetically Modulating Multiple Mechanisms

Author(s): Kenneth K.W. To* and William C.S. Cho

Volume 21, Issue 4, 2021

Published on: 02 February, 2021

Page: [289 - 305] Pages: 17

DOI: 10.2174/1568009621666210203111220

Price: $65


Drug resistance is the major reason accounting for the treatment failure in cancer chemotherapy. Dysregulation of the epigenetic machineries is known to induce chemoresistance. It was reported that numerous genes encoding the key mediators in cancer proliferation, apoptosis, DNA repair, and drug efflux are dysregulated in resistant cancer cells by aberrant DNA methylation. The imbalance of various enzymes catalyzing histone post-translational modifications is also known to alter chromatin configuration and regulate multiple drug resistance genes. Alteration in miRNA signature in cancer cells also gives rise to chemoresistance. Flavonoids are a large group of naturally occurring polyphenolic compounds ubiquitously found in plants, fruits, vegetables and traditional herbs. There has been increasing research interest in the health-promoting effects of flavonoids. Flavonoids were shown to directly kill or re-sensitize resistant cancer cells to conventional anticancer drugs by epigenetic mechanisms. In this review, we summarize the current findings of the circumvention of drug resistance by flavonoids through correcting the aberrant epigenetic regulation of multiple resistance mechanisms. More investigations including the evaluation of synergistic anticancer activity, dosing sequence effect, toxicity in normal cells, and animal studies, are warranted to establish the full potential of the combination of flavonoids with conventional chemotherapeutic drugs in the treatment of cancer with drug resistance.

Keywords: DNA methylation, epigenetic therapy, flavonoids, histone modifications, multidrug resistance, cancer chemotherapy.

Graphical Abstract
Miranda Furtado, C.L.; Dos Santos Luciano, M.C.; Silva Santos, R.D.; Furtado, G.P.; Moraes, M.O.; Pessoa, C. Epidrugs: targeting epigenetic marks in cancer treatment. Epigenetics, 2019, 14(12), 1164-1176.
[] [PMID: 31282279]
Panche, A.N.; Diwan, A.D.; Chandra, S.R. Flavonoids: an overview. J. Nutr. Sci., 2016, 5, e47.
[] [PMID: 28620474]
Raffa, D.; Maggio, B.; Raimondi, M.V.; Plescia, F.; Daidone, G. Recent discoveries of anticancer flavonoids. Eur. J. Med. Chem., 2017, 142, 213-228.
[] [PMID: 28793973]
Ross, J.A.; Kasum, C.M. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu. Rev. Nutr., 2002, 22, 19-34.
[] [PMID: 12055336]
Veeramuthu, D.; Raja, W.; Al-Dhabi, N.A.; Savarimuthu, I. Flavonoids: Anticancer Properties.Flavonoids – From Biosynthesis to Human Health; Goncalo. Justino Intech. Open, 2017
Pietta, P.G. Flavonoids as antioxidants. J. Nat. Prod., 2000, 63(7), 1035-1042.
[] [PMID: 10924197]
Kim, Y.; Keogh, J.B.; Clifton, P.M. Polyphenols and glycemic control. Nutrients, 2016, 8(1), 17.
[] [PMID: 26742071]
Gupta, T.; Das, N.; Imran, S. The prevention and therapy of osteoporosis: A review on emerging trends from hormonal therapy to synthetic drugs to plant-based bioactives. J. Diet. Suppl., 2019, 16(6), 699-713.
[] [PMID: 29985715]
Maher, P. The potential of flavonoids for the treatment of neurodegenerative diseases. Int. J. Mol. Sci., 2019, 20(12), 3056.
[] [PMID: 31234550]
Abotaleb, M.; Samuel, S.M.; Varghese, E.; Varghese, S.; Kubatka, P.; Liskova, A.; Büsselberg, D. Flavonoids in cancer and apoptosis. Cancers (Basel), 2018, 11(1), 28.
[] [PMID: 30597838]
Imran, M.; Gondal, T.A.; Atif, M.; Shahbaz, M.; Qaisarani, T.B.; Mughal, M.H.; Salehi, B.; Martorell, M.; Sharifi-Rad, J. Apigenin as anticancer agent. Phytother. Res., 2019, 2020, 1-17.
[PMID: 32059077]
Jones, P.L.; Veenstra, G.J.; Wade, P.A.; Vermaak, D.; Kass, S.U.; Landsberger, N.; Strouboulis, J.; Wolffe, A.P. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet., 1998, 19(2), 187-191.
[] [PMID: 9620779]
Luo, C.; Hajkova, P.; Ecker, J.R. Dynamic DNA methylation: In the right place at the right time. Science, 2018, 361(6409), 1336-1340.
[] [PMID: 30262495]
Liang, G.; Weisenberger, D.J. DNA methylation aberrancies as a guide for surveillance and treatment of human cancers. Epigenetics, 2017, 12(6), 416-432.
[] [PMID: 28358281]
Wade, P.A. Methyl CpG-binding proteins and transcriptional repression. BioEssays, 2001, 23(12), 1131-1137.
[] [PMID: 11746232]
Héberlé, É.; Bardet, A.F. Sensitivity of transcription factors to DNA methylation. Essays Biochem., 2019, 63(6), 727-741.
[] [PMID: 31755929]
Stancheva, I. Caught in conspiracy: cooperation between DNA methylation and histone H3K9 methylation in the establishment and maintenance of heterochromatin. Biochem. Cell Biol., 2005, 83(3), 385-395.
[] [PMID: 15959564]
Rasmussen, K.D.; Helin, K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev., 2016, 30(7), 733-750.
[] [PMID: 27036965]
Cao, J.Z.; Hains, A.E.; Godley, L.A. Regulation of 5-hydroxymethylcytosine distribution by the TET enzymes.The DNA, RNA, and the Histone Methylomes. RNA Technologies; Jurga, S.; Barciszewski, J., Eds.; Springer: Cham, 2019.
Lio, C.J.; Yuita, H.; Rao, A. Dysregulation of the TET family of epigenetic regulators in lymphoid and myeloid malignancies. Blood, 2019, 134(18), 1487-1497.
[] [PMID: 31467060]
Tolsma, T.O.; Hansen, J.C. Post-translational modifications and chromatin dynamics. Essays Biochem., 2019, 63(1), 89-96.
[] [PMID: 31015385]
Chrun, E.S.; Modolo, F.; Daniel, F.I. Histone modifications: A review about the presence of this epigenetic phenomenon in carcinogenesis. Pathol. Res. Pract., 2017, 213(11), 1329-1339.
[] [PMID: 28882400]
Cappellacci, L.; Perinelli, D.R.; Maggi, F.; Grifantini, M.; Petrelli, R. Recent progress in histone deacetylase inhibitors as anticancer agents. Curr. Med. Chem., 2018.
[] [PMID: 30332940]
Zhang, T.; Cooper, S.; Brockdorff, N. The interplay of histone modifications - writers that read. EMBO Rep., 2015, 16(11), 1467-1481.
[] [PMID: 26474904]
Banerjee, T.; Chakravarti, D. A peek into the complex realm of histone phosphorylation. Mol. Cell. Biol., 2011, 31(24), 4858-4873.
[] [PMID: 22006017]
Gil, R.S.; Vagnarelli, P. Protein phosphatases in chromatin structure and function. Biochim. Biophys. Acta Mol. Cell Res., 2019, 1866(1), 90-101.
[] [PMID: 30036566]
Zhao, Z.; Shilatifard, A. Epigenetic modifications of histones in cancer. Genome Biol., 2019, 20(1), 245.
[] [PMID: 31747960]
Weake, V.M.; Workman, J.L. Histone ubiquitination: triggering gene activity. Mol. Cell, 2008, 29(6), 653-663.
[] [PMID: 18374642]
Jenuwein, T.; Allis, C.D. Translating the histone code. Science, 2001, 293(5532), 1074-1080.
[] [PMID: 11498575]
Esteller, M. Epigenetics in cancer. N. Engl. J. Med., 2008, 358(11), 1148-1159.
[] [PMID: 18337604]
Biswas, S.; Rao, C.M. Epigenetics in cancer: Fundamentals and Beyond. Pharmacol. Ther., 2017, 173, 118-134.
[] [PMID: 28188812]
Quévillon Huberdeau, M.; Simard, M.J. A guide to microRNA-mediated gene silencing. FEBS J., 2019, 286(4), 642-652.
[] [PMID: 30267606]
Acunzo, M.; Romano, G.; Wernicke, D.; Croce, C.M. MicroRNA and cancer- a brief overview. Adv. Biol. Regul., 2015, 57, 1-9.
[] [PMID: 25294678]
Di Leva, G.; Garofalo, M.; Croce, C.M. MicroRNAs in cancer. Annu. Rev. Pathol., 2014, 9, 287-314.
[] [PMID: 24079833]
To, K.K.; Tong, C.W.; Wu, M.; Cho, W.C. MicroRNAs in the prognosis and therapy of colorectal cancer: From bench to bedside. World J. Gastroenterol., 2018, 24(27), 2949-2973.
[] [PMID: 30038463]
Assaraf, Y.G.; Brozovic, A.; Gonçalves, A.C.; Jurkovicova, D.; Linē, A.; Machuqueiro, M.; Saponara, S.; Sarmento-Ribeiro, A.B.; Xavier, C.P.R.; Vasconcelos, M.H. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resist. Updat., 2019, 46, 100645.
[] [PMID: 31585396]
Shah, K.; Rawal, R.M. Genetic and epigenetic modulation of drug resistance in cancer: Challenges and opportunities. Curr. Drug Metab., 2019, 20(14), 1114-1131.
[] [PMID: 31902353]
Mansoori, B.; Mohammadi, A.; Davudian, S.; Shirjang, S.; Baradaran, B. The different mechanisms of cancer drug resistance: A brief review. Adv. Pharm. Bull., 2017, 7(3), 339-348.
[] [PMID: 29071215]
Marmorstein, R.; Trievel, R.C. Histone modifying enzymes: structures, mechanisms, and specificities. Biochim. Biophys. Acta, 2009, 1789(1), 58-68.
[] [PMID: 18722564]
Nair, S.S.; Kumar, R. Chromatin remodeling in cancer: a gateway to regulate gene transcription. Mol. Oncol., 2012, 6(6), 611-619.
[] [PMID: 23127546]
Weichert, W. HDAC expression and clinical prognosis in human malignancies. Cancer Lett., 2009, 280(2), 168-176.
[] [PMID: 19103471]
Mithraprabhu, S.; Kalff, A.; Chow, A.; Khong, T.; Spencer, A. Dysregulated Class I histone deacetylases are indicators of poor prognosis in multiple myeloma. Epigenetics, 2014, 9(11), 1511-1520.
[] [PMID: 25482492]
Van Damme, M.; Crompot, E.; Meuleman, N.; Mineur, P.; Bron, D.; Lagneaux, L.; Stamatopoulos, B. HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance. Epigenetics, 2012, 7(12), 1403-1412.
[] [PMID: 23108383]
Sharda, A.; Rashid, M.; Shah, S.G.; Sharma, A.K.; Singh, S.R.; Gera, P.; Chilkapati, M.K.; Gupta, S. Elevated HDAC activity and altered histone phospho-acetylation confer acquired radio-resistant phenotype to breast cancer cells. Clin. Epigenetics, 2020, 12(1), 4.
[] [PMID: 31900196]
Gan, L.; Yang, Y.; Li, Q.; Feng, Y.; Liu, T.; Guo, W. Epigenetic regulation of cancer progression by EZH2: from biological insights to therapeutic potential. Biomark. Res., 2018, 6, 10.
[] [PMID: 29556394]
Gates, L.A.; Foulds, C.E.; O’Malley, B.W. Histone marks in the “driver’s seat”: Functional roles in steering the transcription cycle. Trends Biochem. Sci., 2017, 42(12), 977-989.
[] [PMID: 29122461]
Chen, Z.; Yang, P.; Li, W.; He, F.; Wei, J.; Zhang, T.; Zhong, J.; Chen, H.; Cao, J. Expression of EZH2 is associated with poor outcome in colorectal cancer. Oncol. Lett., 2018, 15(3), 2953-2961.
[PMID: 29435024]
Chang, J.W.; Gwak, S.Y.; Shim, G.A.; Liu, L.; Lim, Y.C.; Kim, J.M.; Jung, M.G.; Koo, B.S. EZH2 is associated with poor prognosis in head-and-neck squamous cell carcinoma via regulating the epithelial-to-mesenchymal transition and chemosensitivity. Oral Oncol., 2016, 52, 66-74.
[] [PMID: 26604082]
An, X.; Sarmiento, C.; Tan, T.; Zhu, H. Regulation of multidrug resistance by microRNAs in anti-cancer therapy. Acta Pharm. Sin. B, 2017, 7(1), 38-51.
[] [PMID: 28119807]
Cui, Q.; Wang, J.Q.; Assaraf, Y.G.; Ren, L.; Gupta, P.; Wei, L.; Ashby, C.R., Jr; Yang, D.H.; Chen, Z.S. Modulating ROS to overcome multidrug resistance in cancer. Drug Resist. Updat., 2018, 41, 1-25.
[] [PMID: 30471641]
Busch, C.; Burkard, M.; Leischner, C.; Lauer, U.M.; Frank, J.; Venturelli, S. Epigenetic activities of flavonoids in the prevention and treatment of cancer. Clin. Epigenetics, 2015, 7, 64.
[] [PMID: 26161152]
Supic, G.; Jagodic, M.; Magic, Z. Epigenetics: a new link between nutrition and cancer. Nutr. Cancer, 2013, 65(6), 781-792.
[] [PMID: 23909721]
Supic, G.; Wagner, D.; Magic, Z. Epigenetic impact of bioactive dietary compounds in cancer chemoprevention.Critical Dietary Factors in Cancer Chemoprevention; Ullah, M.F.; Ahmad, A., Eds.; 153-181.
Kanwal, R.; Datt, M.; Liu, X.; Gupta, S. Dietary flavones as dual inhibitors of DNA methyltransferases and histone methyltransferases. PLoS One, 2016, 11(9), e0162956.
[] [PMID: 27658199]
Pradhan, N.; Sengupta, D.; Patra, S.K. Epigenetic dietary intervention for prevention of cancer. Epigenetics of Cancer Prevention; Bishayee, A.; Bhatia, D., Eds.; Elsevier Inc: Netherlands, 2019.
Andrijauskaite, K.; Morris, J.; Wargovich, M.J. Natural anticancer agents. Epigenetics of Cancer Prevention; Bishayee, A.; Bhatia, D., Eds.; Elsevier Inc: Netherlands, 2019.
Akbari Kordkheyli, V.; Khonakdar Tarsi, A.; Mishan, M.A.; Tafazoli, A.; Bardania, H.; Zarpou, S.; Bagheri, A. Effects of quercetin on microRNAs: A mechanistic review. J. Cell. Biochem., 2019, 120(8), 12141-12155.
[] [PMID: 30957271]
Lee, W.J.; Shim, J.Y.; Zhu, B.T. Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol. Pharmacol., 2005, 68(4), 1018-1030.
[] [PMID: 16037419]
Sharma, V.; Kumar, L.; Mohanty, S.K.; Maikhuri, J.P.; Rajender, S.; Gupta, G. Sensitization of androgen refractory prostate cancer cells to anti-androgens through re-expression of epigenetically repressed androgen receptor - Synergistic action of quercetin and curcumin. Mol. Cell. Endocrinol., 2016, 431, 12-23.
[] [PMID: 27132804]
Tan, S.; Wang, C.; Lu, C.; Zhao, B.; Cui, Y.; Shi, X.; Ma, X. Quercetin is able to demethylate the p16INK4a gene promoter. Chemotherapy, 2009, 55(1), 6-10.
[] [PMID: 18974642]
Lee, W.J.; Chen, Y.R.; Tseng, T.H. Quercetin induces FasL-related apoptosis, in part, through promotion of histone H3 acetylation in human leukemia HL-60 cells. Oncol. Rep., 2011, 25(2), 583-591.
[PMID: 21165570]
Zheng, N.G.; Wang, J.L.; Yang, S.L.; Wu, J.L. Aberrant epigenetic alteration in Eca9706 cells modulated by nanoliposomal quercetin combined with butyrate mediated via epigenetic-NF-κB signaling. Asian Pac. J. Cancer Prev., 2014, 15(11), 4539-4543.
[] [PMID: 24969881]
Kedhari Sundaram, M.; Hussain, A.; Haque, S.; Raina, R.; Afroze, N. Quercetin modifies 5'CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells. J. Cell. Biochem., 2019, 120(10), 18357-18369.
[] [PMID: 31172592]
Zhang, X.; Guo, Q.; Chen, J.; Chen, Z. Quercetin enhances cisplatin sensitivity of human osteosarcoma cells by modulating microRNA-217-KRAS axis. Mol. Cells, 2015, 38(7), 638-642.
[] [PMID: 26062553]
Sayeed, M.A.; Bracci, M.; Lucarini, G.; Lazzarini, R.; Di Primio, R.; Santarelli, L. Regulation of microRNA using promising dietary phytochemicals: Possible preventive and treatment option of malignant mesothelioma. Biomed. Pharmacother., 2017, 94, 1197-1224.
[] [PMID: 28841784]
Perillo, B.; Di Donato, M.; Pezone, A.; Di Zazzo, E.; Giovannelli, P.; Galasso, G.; Castoria, G.; Migliaccio, A. ROS in cancer therapy: the bright side of the moon. Exp. Mol. Med., 2020, 52(2), 192-203.
[] [PMID: 32060354]
Kirkpatrick, D.L.; Powis, G. Clinically evaluated cancer drugs inhibiting redox signaling. Antioxid. Redox Signal., 2017, 26(6), 262-273.
[] [PMID: 26983373]
Rajaraman, P.; Hutchinson, A.; Rothman, N.; Black, P.M.; Fine, H.A.; Loeffler, J.S.; Selker, R.G.; Shapiro, W.R.; Linet, M.S.; Inskip, P.D. Oxidative response gene polymorphisms and risk of adult brain tumors. Neuro-oncol., 2008, 10(5), 709-715.
[] [PMID: 18682580]
Vidak, M.; Rozman, D.; Komel, R. Effects of flavonoids from food and dietary supplements on glial and glioblastoma multiforme cells. Molecules, 2015, 20(10), 19406-19432.
[] [PMID: 26512639]
Rinaldi, M.; Caffo, M.; Minutoli, L.; Marini, H.; Abbritti, R.V.; Squadrito, F.; Trichilo, V.; Valenti, A.; Barresi, V.; Altavilla, D.; Passalacqua, M.; Caruso, G. ROS and brain gliomas: An overview of potential and innovative therapeutic strategies. Int. J. Mol. Sci., 2016, 17(6), 984.
[] [PMID: 27338365]
Malireddy, S.; Kotha, S.R.; Secor, J.D.; Gurney, T.O.; Abbott, J.L.; Maulik, G.; Maddipati, K.R.; Parinandi, N.L. Phytochemical antioxidants modulate mammalian cellular epigenome: implications in health and disease. Antioxid. Redox Signal., 2012, 17(2), 327-339.
[] [PMID: 22404530]
Shilpi, A.; Parbin, S.; Sengupta, D.; Kar, S.; Deb, M.; Rath, S.K.; Pradhan, N.; Rakshit, M.; Patra, S.K. Mechanisms of DNA methyltransferase-inhibitor interactions: Procyanidin B2 shows new promise for therapeutic intervention of cancer. Chem. Biol. Interact., 2015, 233, 122-138.
[] [PMID: 25839702]
Li, Y.; Meeran, S.M.; Tollefsbol, T.O. Combinatorial bioactive botanicals re-sensitize tamoxifen treatment in ER-negative breast cancer via epigenetic reactivation of ERα expression. Sci. Rep., 2017, 7(1), 9345.
[] [PMID: 28839265]
Saldanha, S.N.; Kala, R.; Tollefsbol, T.O. Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate. Exp. Cell Res., 2014, 324(1), 40-53.
[] [PMID: 24518414]
Moseley, V.R.; Morris, J.; Knackstedt, R.W.; Wargovich, M.J. Green tea polyphenol epigallocatechin 3-gallate, contributes to the degradation of DNMT3A and HDAC3 in HCT 116 human colon cancer cells. Anticancer Res., 2013, 33(12), 5325-5333.
[PMID: 24324066]
Wang, W.; Qin, J.J.; Voruganti, S.; Nag, S.; Zhou, J.; Zhang, R. Polycomb group. (PcG) proteins and human cancers: Multifaceted functions and therapeutic implications. Med. Res. Rev., 2015, 35(6), 1220-1267.
[] [PMID: 26227500]
Choudhury, S.R.; Balasubramanian, S.; Chew, Y.C.; Han, B.; Marquez, V.E.; Eckert, R.L. (-)-Epigallocatechin-3-gallate and DZNep reduce polycomb protein level via a proteasome-dependent mechanism in skin cancer cells. Carcinogenesis, 2011, 32(10), 1525-1532.
[] [PMID: 21798853]
Li, G.X.; Chen, Y.K.; Hou, Z.; Xiao, H.; Jin, H.; Lu, G.; Lee, M.J.; Liu, B.; Guan, F.; Yang, Z.; Yu, A.; Yang, C.S. Pro-oxidative activities and dose-response relationship of (-)-epigallocatechin-3-gallate in the inhibition of lung cancer cell growth: a comparative study in vivo and in vitro. Carcinogenesis, 2010, 31(5), 902-910.
[] [PMID: 20159951]
Zhou, D.H.; Wang, X.; Feng, Q. EGCG enhances the efficacy of cisplatin by downregulating hsa-miR-98-5p in NSCLC A549 cells. Nutr. Cancer, 2014, 66(4), 636-644.
[] [PMID: 24712372]
La, X.; Zhang, L.; Li, Z.; Li, H.; Yang, Y. (-)-Epigallocatechin gallate (EGCG) enhances the sensitivity of colorectal cancer cells to 5-FU by inhibiting GRP78/NF-kB/miR-155-5p/MDR1 pathway. J. Agric. Food Chem., 2019, 67(9), 2510-2518.
[] [PMID: 30741544]
Sharma, H.; Kanwal, R.; Bhaskaran, N.; Gupta, S. Plant flavone apigenin binds to nucleic acid bases and reduces oxidative DNA damage in prostate epithelial cells. PLoS One, 2014, 9(3), e91588.
[] [PMID: 24614817]
Paredes-Gonzalez, X.; Fuentes, F.; Su, Z.Y.; Kong, A.N. Apigenin reactivates Nrf2 anti-oxidative stress signaling in mouse skin epidermal JB6 P + cells through epigenetics modifications. AAPS J., 2014, 16(4), 727-735.
[] [PMID: 24830944]
Tseng, T.H.; Chien, M.H.; Lin, W.L.; Wen, Y.C.; Chow, J.M.; Chen, C.K.; Kuo, T.C.; Lee, W.J. Inhibition of MDA-MB-231 breast cancer cell proliferation and tumor growth by apigenin through induction of G2/M arrest and histone H3 acetylation-mediated p21WAF1/CIP1 expression. Environ. Toxicol., 2017, 32(2), 434-444.
[] [PMID: 26872304]
Pandey, M.; Kaur, P.; Shukla, S.; Abbas, A.; Fu, P.; Gupta, S. Plant flavone apigenin inhibits HDAC and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells: in vitro and in vivo study. Mol. Carcinog., 2012, 51(12), 952-962.
[] [PMID: 22006862]
Pan, M.R.; Hsu, M.C.; Chen, L.T.; Hung, W.C. Orchestration of H3K27 methylation: mechanisms and therapeutic implication. Cell. Mol. Life Sci., 2018, 75(2), 209-223.
[] [PMID: 28717873]
Hyun, K.; Jeon, J.; Park, K.; Kim, J. Writing, erasing and reading histone lysine methylations. Exp. Mol. Med., 2017, 49(4), e324.
[] [PMID: 28450737]
Gao, A.M.; Zhang, X.Y.; Hu, J.N.; Ke, Z.P. Apigenin sensitizes hepatocellular carcinoma cells to doxorubic through regulating miR-520b/ATG7 axis. Chem. Biol. Interact., 2018, 280, 45-50.
[] [PMID: 29191453]
Ozbey, U.; Attar, R.; Romero, M.A.; Alhewairini, S.S.; Afshar, B.; Sabitaliyevich, U.Y.; Hanna-Wakim, L.; Ozcelik, B.; Farooqi, A.A. Apigenin as an effective anticancer natural product: Spotlight on TRAIL, WNT/β-catenin, JAK-STAT pathways, and microRNAs. J. Cell. Biochem., 2018, 120, 1060-1067.
[] [PMID: 30278099]
Hagiwara, K.; Kosaka, N.; Yoshioka, Y.; Takahashi, R.U.; Takeshita, F.; Ochiya, T. Stilbene derivatives promote Ago2-dependent tumour-suppressive microRNA activity. Sci. Rep., 2012, 2, 314.
[] [PMID: 22423322]
Qiu, W.; Lin, J.; Zhu, Y.; Zhang, J.; Zeng, L.; Su, M.; Tian, Y. Kaempferol modulates DNA methylation and downregulates DNMT3b in bladder cancer. Cell. Physiol. Biochem., 2017, 41(4), 1325-1335.
[] [PMID: 28278502]
Berger, A.; Venturelli, S.; Kallnischkies, M.; Böcker, A.; Busch, C.; Weiland, T.; Noor, S.; Leischner, C.; Weiss, T.S.; Lauer, U.M.; Bischoff, S.C.; Bitzer, M. Kaempferol, a new nutrition-derived pan-inhibitor of human histone deacetylases. J. Nutr. Biochem., 2013, 24(6), 977-985.
[] [PMID: 23159065]
Han, X.; Liu, C.F.; Gao, N.; Zhao, J.; Xu, J. Kaempferol suppresses proliferation but increases apoptosis and autophagy by up-regulating microRNA-340 in human lung cancer cells. Biomed. Pharmacother., 2018, 108, 809-816.
[] [PMID: 30253373]
Godoy, L.D.; Lucas, J.E.; Bender, A.J.; Romanick, S.S.; Ferguson, B.S. Targeting the epigenome: Screening bioactive compounds that regulate histone deacetylase activity. Mol. Nutr. Food Res., 2017, 61(4)
[] [PMID: 27981795]
Basu Mallik, S.; Pai, A.; Shenoy, R.R.; Jayashree, B.S. Novel flavonol analogues as potential inhibitors of JMJD3 histone demethylase-A study based on molecular modelling. J. Mol. Graph. Model., 2017, 72, 81-87.
[] [PMID: 28064082]
Dong, X.; Zhang, J.; Yang, F.; Wu, J.; Cai, R.; Wang, T.; Zhang, J. Effect of luteolin on the methylation status of the OPCML gene and cell growth in breast cancer cells. Exp. Ther. Med., 2018, 16(4), 3186-3194.
[] [PMID: 30214542]
Kang, K.A.; Piao, M.J.; Hyun, Y.J.; Zhen, A.X.; Cho, S.J.; Ahn, M.J.; Yi, J.M.; Hyun, J.W. 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.
[] [PMID: 30988303]
Gao, G.; Ge, R.; Li, Y.; Liu, S. Luteolin exhibits anti-breast cancer property through up-regulating miR-203. Artif. Cells Nanomed. Biotechnol., 2019, 47(1), 3265-3271.
[] [PMID: 31368817]
Setchell, K.D.; Brown, N.M.; Zimmer-Nechemias, L.; Brashear, W.T.; Wolfe, B.E.; Kirschner, A.S.; Heubi, J.E. Evidence for lack of absorption of soy isoflavone glycosides in humans, supporting the crucial role of intestinal metabolism for bioavailability. Am. J. Clin. Nutr., 2002, 76(2), 447-453.
[] [PMID: 12145021]
Karsli-Ceppioglu, S.; Ngollo, M.; Adjakly, M.; Dagdemir, A.; Judes, G.; Lebert, A.; Boiteux, J.P.; Penault-LLorca, F.; Bignon, Y.J.; Guy, L.; Bernard-Gallon, D. Genome-wide DNA methylation modified by soy phytoestrogens: role for epigenetic therapeutics in prostate cancer? OMICS, 2015, 19(4), 209-219.
[] [PMID: 25831061]
Bosviel, R.; Dumollard, E.; Déchelotte, P.; Bignon, Y.J.; Bernard- Gallon, D. Can soy phytoestrogens decrease DNA methylation in BRCA1 and BRCA2 oncosuppressor genes in breast cancer? OMICS, 2012, 16(5), 235-244.
[] [PMID: 22339411]
Li, Y.; Kong, D.; Ahmad, A.; Bao, B.; Dyson, G.; Sarkar, F.H. Epigenetic deregulation of miR-29a and miR-1256 by isoflavone contributes to the inhibition of prostate cancer cell growth and invasion. Epigenetics, 2012, 7(8), 940-949.
[] [PMID: 22805767]
Dagdemir, A.; Durif, J.; Ngollo, M.; Bignon, Y.J.; Bernard-Gallon, D. Histone lysine trimethylation or acetylation can be modulated by phytoestrogen, estrogen or anti-HDAC in breast cancer cell lines. Epigenomics, 2013, 5(1), 51-63.
[] [PMID: 23414320]
Kondo, Y.; Shen, L.; Cheng, A.S.; Ahmed, S.; Boumber, Y.; Charo, C.; Yamochi, T.; Urano, T.; Furukawa, K.; Kwabi-Addo, B.; Gold, D.L.; Sekido, Y.; Huang, T.H.; Issa, J.P. Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat. Genet., 2008, 40(6), 741-750.
[] [PMID: 18488029]
Cheng, C.; Qin, Y.; Zhi, Q.; Wang, J.; Qin, C. Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3K/Akt and Wnt/β-catenin signaling pathways by up-regulating miR-34a. Int. J. Biol. Macromol., 2018, 107(Pt B), 2620-2629.
[] [PMID: 29080815]
Chiyomaru, T.; Yamamura, S.; Fukuhara, S.; Yoshino, H.; Kinoshita, T.; Majid, S.; Saini, S.; Chang, I.; Tanaka, Y.; Enokida, H.; Seki, N.; Nakagawa, M.; Dahiya, R. Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR. PLoS One, 2013, 8(8), e70372.
[] [PMID: 23936419]
Mahmoud, A.M.; Ali, M.M. Methyl donor micronutrients that modify DNA methylation and cancer outcome. Nutrients, 2019, 11(3), 608.
[] [PMID: 30871166]
Zhang, J.; Zheng, Y.G. SAM/SAH analogs as versatile tools for SAM-dependent methyltransferases. ACS Chem. Biol., 2016, 11(3), 583-597.
[] [PMID: 26540123]
Mentch, S.J.; Locasale, J.W. One-carbon metabolism and epigenetics: understanding the specificity. Ann. N. Y. Acad. Sci., 2016, 1363, 91-98.
[] [PMID: 26647078]
Thakur, V.S.; Deb, G.; Babcook, M.A.; Gupta, S. Plant phytochemicals as epigenetic modulators: role in cancer chemoprevention. AAPS J., 2014, 16(1), 151-163.
[] [PMID: 24307610]
Gilbert, E.R.; Liu, D. Flavonoids influence epigenetic-modifying enzyme activity: structure - function relationships and the therapeutic potential for cancer. Curr. Med. Chem., 2010, 17(17), 1756-1768.
[] [PMID: 20345345]
Choi, K.C.; Jung, M.G.; Lee, Y.H.; Yoon, J.C.; Kwon, S.H.; Kang, H.B.; Kim, M.J.; Cha, J.H.; Kim, Y.J.; Jun, W.J.; Lee, J.M.; Yoon, H.G. Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation. Cancer Res., 2009, 69(2), 583-592.
[] [PMID: 19147572]
Dashwood, R.H.; Myzak, M.C.; Ho, E. Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention? Carcinogenesis, 2006, 27(2), 344-349.
[] [PMID: 16267097]
Howitz, K.T.; Bitterman, K.J.; Cohen, H.Y.; Lamming, D.W.; Lavu, S.; Wood, J.G.; Zipkin, R.E.; Chung, P.; Kisielewski, A.; Zhang, L.L.; Scherer, B.; Sinclair, D.A. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 2003, 425(6954), 191-196.
[] [PMID: 12939617]
Menezes, J.C.; Orlikova, B.; Morceau, F.; Diederich, M. Natural and synthetic flavonoids: Structure-activity relationship and chemotherapeutic potential for the treatment of leukemia. Crit. Rev. Food Sci. Nutr., 2016, 56(Suppl. 1), S4-S28.
[] [PMID: 26463658]
Baselga-Escudero, L.; Arola-Arnal, A.; Pascual-Serrano, A.; Ribas-Latre, A.; Casanova, E.; Salvadó, M.J.; Arola, L.; Blade, C. Chronic administration of proanthocyanidins or docosahexaenoic acid reverses the increase of miR-33a and miR-122 in dyslipidemic obese rats. PLoS One, 2013, 8(7), e69817.
[] [PMID: 23922812]
Fraga, C.G.; Galleano, M.; Verstraeten, S.V.; Oteiza, P.I. Basic biochemical mechanisms behind the health benefits of polyphenols. Mol. Aspects Med., 2010, 31(6), 435-445.
[] [PMID: 20854840]
Chendrimada, T.P.; Gregory, R.I.; Kumaraswamy, E.; Norman, J.; Cooch, N.; Nishikura, K.; Shiekhattar, R. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature, 2005, 436(7051), 740-744.
[] [PMID: 15973356]
George, J.; Singh, M.; Srivastava, A.K.; Bhui, K.; Roy, P.; Chaturvedi, P.K.; Shukla, Y. Resveratrol and black tea polyphenol combination synergistically suppress mouse skin tumors growth by inhibition of activated MAPKs and p53. PLoS One, 2011, 6(8), e23395.
[] [PMID: 21887248]
Hoensch, H.; Groh, B.; Edler, L.; Kirch, W. Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence. World J. Gastroenterol., 2008, 14(14), 2187-2193.
[] [PMID: 18407592]
Paller, C.J.; Rudek, M.A.; Zhou, X.C.; Wagner, W.D.; Hudson, T.S.; Anders, N.; Hammers, H.J.; Dowling, D.; King, S.; Antonarakis, E.S.; Drake, C.G.; Eisenberger, M.A.; Denmeade, S.R.; Rosner, G.L.; Carducci, M.A. A phase I study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: Safety, tolerability, and dose determination. Prostate, 2015, 75(14), 1518-1525.
[] [PMID: 26012728]
Lemanne, D.; Block, K.I.; Kressel, B.R.; Sukhatme, V.P.; White, J.D. A case of complete and durable molecular remission of chronic lymphocytic leukemia following treatment with epigallocatechin-3-gallate, an extract of green tea. Cureus, 2015, 7(12), e441.
[] [PMID: 26858922]
Zhao, H.; Zhu, W.; Jia, L.; Sun, X.; Chen, G.; Zhao, X.; Li, X.; Meng, X.; Kong, L.; Xing, L.; Yu, J. Phase I study of topical epigallocatechin-3-gallate (EGCG) in patients with breast cancer receiving adjuvant radiotherapy. Br. J. Radiol., 2016, 89(1058), 20150665.
[] [PMID: 26607642]
Ide, H.; Tokiwa, S.; Sakamaki, K.; Nishio, K.; Isotani, S.; Muto, S.; Hama, T.; Masuda, H.; Horie, S. Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate, 2010, 70(10), 1127-1133.
[] [PMID: 20503397]
Shike, M.; Doane, A.S.; Russo, L.; Cabal, R.; Reis-Filho, J.S.; Gerald, W.; Cody, H.; Khanin, R.; Bromberg, J.; Norton, L. The effects of soy supplementation on gene expression in breast cancer: a randomized placebo-controlled study. J. Natl. Cancer Inst., 2014, 106(9), dju189.
[] [PMID: 25190728]
Touillaud, M.S.; Pillow, P.C.; Jakovljevic, J.; Bondy, M.L.; Singletary, S.E.; Li, D.; Chang, S. Effect of dietary intake of phytoestrogens on estrogen receptor status in premenopausal women with breast cancer. Nutr. Cancer, 2005, 51(2), 162-169.
[] [PMID: 15860438]
Lazarevic, B.; Hammarström, C.; Yang, J.; Ramberg, H.; Diep, L.M.; Karlsen, S.J.; Kucuk, O.; Saatcioglu, F.; Taskèn, K.A.; Svindland, A. The effects of short-term genistein intervention on prostate biomarker expression in patients with localised prostate cancer before radical prostatectomy. Br. J. Nutr., 2012, 108(12), 2138-2147.
[] [PMID: 22397815]
Arora, I.; Sharma, M.; Tollefsbol, T.O. Combinatorial epigenetics impact of polyphenols and phytochemicals in cancer prevention and therapy. Int. J. Mol. Sci., 2019, 20(18), 4567.
[] [PMID: 31540128]
Myzak, M.C.; Tong, P.; Dashwood, W.M.; Dashwood, R.H.; Ho, E. Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects. Exp. Biol. Med. (Maywood), 2007, 232(2), 227-234.
[PMID: 17259330]
Bates, S.E.; Zhan, Z.; Steadman, K.; Obrzut, T.; Luchenko, V.; Frye, R.; Robey, R.W.; Turner, M.; Gardner, E.R.; Figg, W.D.; Steinberg, S.M.; Ling, A.; Fojo, T.; To, K.W.; Piekarz, R.L. Laboratory correlates for a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma. Br. J. Haematol., 2010, 148(2), 256-267.
[] [PMID: 19874311]
Alvarez, A.I.; Real, R.; Pérez, M.; Mendoza, G.; Prieto, J.G.; Merino, G. Modulation of the activity of ABC transporters (P-glycoprotein, MRP2, BCRP) by flavonoids and drug response. J. Pharm. Sci., 2010, 99(2), 598-617.
[] [PMID: 19544374]
Leslie, E.M.; Mao, Q.; Oleschuk, C.J.; Deeley, R.G.; Cole, S.P. Modulation of multidrug resistance protein 1 (MRP1/ABCC1) transport and atpase activities by interaction with dietary flavonoids. Mol. Pharmacol., 2001, 59(5), 1171-1180.
[] [PMID: 11306701]
Cooray, H.C.; Janvilisri, T.; van Veen, H.W.; Hladky, S.B.; Barrand, M.A. Interaction of the breast cancer resistance protein with plant polyphenols. Biochem. Biophys. Res. Commun., 2004, 317(1), 269-275.
[] [PMID: 15047179]
Murota, K.; Nakamura, Y.; Uehara, M. Flavonoid metabolism: the interaction of metabolites and gut microbiota. Biosci. Biotechnol. Biochem., 2018, 82(4), 600-610.
[] [PMID: 29504827]
Hostetler, G.L.; Ralston, R.A.; Schwartz, S.J. Flavones: food sources, bioavailability, metabolism, and bioactivity. Adv. Nutr., 2017, 8(3), 423-435.
[] [PMID: 28507008]
Hollman, P.C.H. Absorption, bioavailability and metabolism of flavonoids. Pharm. Biol., 2004, 42, 74-83.
Russo, G.L.; Russo, M.; Spagnuolo, C. The pleiotropic flavonoid quercetin: from its metabolism to the inhibition of protein kinases in chronic lymphocytic leukemia. Food Funct., 2014, 5(10), 2393-2401.
[] [PMID: 25096193]
Russo, G.L.; Russo, M.; Spagnuolo, C.; Tedesco, I.; Bilotto, S.; Iannitti, R.; Palumbo, R. Quercetin: a pleiotropic kinase inhibitor against cancer. Cancer Treat. Res., 2014, 159, 185-205.
[] [PMID: 24114481]
Zhao, J.; Yang, J.; Xie, Y. Improvement strategies for the oral bioavailability of poorly water-soluble flavonoids: An overview. Int. J. Pharm., 2019, 570, 118642.
[] [PMID: 31446024]
Rostami, S.; Nadali, F.; Alibakhshi, R.; Zaker, F.; Nasiri, N.; Payandeh, M.; Chahardouli, B.; Maleki, A. Aberrant methylation of APAF-1 gene in acute leukemia patients. Int. J. Hematol. Oncol. Stem Cell Res., 2017, 11(3), 225-230.
[PMID: 28989589]
Reed, K.; Parissenti, A.M. Epigenetic regulation of ABCB1 transporter expression and function. Curr. Pharmacogenomics Person. Med., 2010, 8, 218-231.
Fröhlich, L.F.; Mrakovcic, M.; Smole, C.; Lahiri, P.; Zatloukal, K. Epigenetic silencing of apoptosis-inducing gene expression can be efficiently overcome by combined SAHA and TRAIL treatment in uterine sarcoma cells. PLoS One, 2014, 9(3), e91558.
[] [PMID: 24618889]
Abdel-Hafiz, H.A. Epigenetic mechanisms of tamoxifen resistance in luminal breast cancer. Diseases, 2017, 5(3), 16.
[] [PMID: 28933369]
Martignano, F.; Gurioli, G.; Salvi, S.; Calistri, D.; Costantini, M.; Gunelli, R.; De Giorgi, U.; Foca, F.; Casadio, V. GSTP1 methylation and protein expression in prostate cancer: Diagnostic implications. Dis. Markers, 2016, 2016, 4358292.
[] [PMID: 27594734]
Lund, R.J.; Huhtinen, K.; Salmi, J.; Rantala, J.; Nguyen, E.V.; Moulder, R.; Goodlett, D.R.; Lahesmaa, R.; Carpén, O. DNA methylation and trascriptome changes associated with cisplatin resistance in ovarian cancer. Sci. Rep., 2017, 7(1), 1469.
[] [PMID: 28473707]
Hegi, M.E.; Diserens, A.C.; Gorlia, T.; Hamou, M.F.; de Tribolet, N.; Weller, M.; Kros, J.M.; Hainfellner, J.A.; Mason, W.; Mariani, L.; Bromberg, J.E.; Hau, P.; Mirimanoff, R.O.; Cairncross, J.G.; Janzer, R.C.; Stupp, R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med., 2005, 352(10), 997-1003.
[] [PMID: 15758010]
García-Gutiérrez, L.; McKenna, S.; Kolch, W.; Matallanas, D. RASSF1A tumor suppressor: Target the network for effective cancer therapy. Cancers (Basel), 2020, 12(1), 229.
[] [PMID: 31963420]
Wang, P.; Henning, S.M.; Heber, D.; Vadgama, J.V. Sensitization to docetaxel in prostate cancer cells by green tea and quercetin. J. Nutr. Biochem., 2015, 26(4), 408-415.
[] [PMID: 25655047]
Zheng, A.W.; Chen, Y.Q.; Zhao, L.Q.; Feng, J.G. Myricetin induces apoptosis and enhances chemosensitivity in ovarian cancer cells. Oncol. Lett., 2017, 13(6), 4974-4978.
[] [PMID: 28588737]
Liu, X.; Sun, C.; Liu, B.; Jin, X.; Li, P.; Zheng, X.; Zhao, T.; Li, F.; Li, Q. Genistein mediates the selective radiosensitizing effect in NSCLC A549 cells via inhibiting methylation of the keap1 gene promoter region. Oncotarget, 2016, 7(19), 27267-27279.
[] [PMID: 27029077]
Mahmoud, A.M.; Al-Alem, U.; Ali, M.M.; Bosland, M.C. Genistein increases estrogen receptor beta expression in prostate cancer via reducing its promoter methylation. J. Steroid Biochem. Mol. Biol., 2015, 152, 62-75.
[] [PMID: 25931004]
Feng, C.; Ho, Y.; Sun, C.; Xia, G.; Ding, Q.; Gu, B. Epigallocatechin gallate inhibits the growth and promotes the apoptosis of bladder cancer cells. Exp. Ther. Med., 2017, 14(4), 3513-3518.
[] [PMID: 29042941]
Meng, J.; Tong, Q.; Liu, X.; Yu, Z.; Zhang, J.; Gao, B. Epigallocatechin-3-gallate inhibits growth and induces apoptosis in esophageal cancer cells through the demethylation and reactivation of the p16 gene. Oncol. Lett., 2017, 14(1), 1152-1156.
[] [PMID: 28693288]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy