Cost-efficacy of currently applied treatments is an issue in overall cancer management challenging healthcare and causing tremendous economic burden to societies around the world. Consequently, complex treatment models presenting concepts of predictive diagnostics followed by targeted prevention and treatments tailored to the personal patient profiles earn global appreciation as benefiting the patient, healthcare economy, and the society at large. In this context, application of flavonoids as a spectrum of compounds and their nano-technologically created derivatives is extensively under consideration, due to their multi-faceted anti-cancer effects applicable to the overall cost-effective cancer management, primary, secondary, and even tertiary prevention. This article analyzes most recently updated data focused on the potent capacity of flavonoids to promote anti-cancer therapeutic effects and interprets all the collected research achievements in the frame-work of predictive, preventive, and personalized (3P) medicine. Main pillars considered are: - Predictable anti-neoplastic, immune-modulating, drug-sensitizing effects; - Targeted molecular pathways to improve therapeutic outcomes by increasing sensitivity of cancer cells and reversing their resistance towards currently applied therapeutic modalities.

Department of Applied Ecology Faculty of Environmental Sciences Czech University of Life Sciences Prague Kamýcká 129 16500 Prague Czech Republic

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava 03601 Martin Slovakia

Department of Obstetrics and Gynecology Jessenius Faculty of Medicine Comenius University in Bratislava 03601 Martin Slovakia

Department of Radiation Oncology University Hospital Bonn Rheinische Friedrich Wilhelms Universität Bonn Bonn Germany

Institute for Health and Sport Victoria University Melbourne 3030 Australia

Musculoskeletal Research Group and Tumor Biology Chair of Vegetative Anatomy Institute of Anatomy Faculty of Medicine Ludwig Maximilian University Munich 80336 Munich Germany

Museum of Literature in Moravia Klášter 1 66461 Rajhrad Czech Republic

Predictive Preventive and Personalised Medicine Department of Radiation Oncology University Hospital Bonn Rheinische Friedrich Wilhelms Universität Bonn 53127 Bonn Germany

Weill Cornell Medicine Qatar Education City Qatar Foundation 24144 Doha Qatar

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Kucera R, Pecen L, Topolcan O, Dahal AR, Costigliola V, Giordano FA, et al. Prostate cancer management: long-term beliefs, epidemic developments in the early twenty-first century and 3PM dimensional solutions. EPMA Journal. 2020;11:399–418. 10.1007/s13167-020-00214-1. PubMed PMC

Koklesova L, Liskova A, Samec M, Qaradakhi T, Zulli A, Smejkal K, et al. Genoprotective activities of plant natural substances in cancer and chemopreventive strategies in the context of 3P medicine. EPMA Journal. 2020;11:261–287. doi: 10.1007/s13167-020-00210-5. PubMed DOI PMC

Samec M, Liskova A, Koklesova L, Samuel SM, Zhai K, Buhrmann C, et al. Flavonoids against the Warburg phenotype—concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism. EPMA J. 2020;11:377–398. doi: 10.1007/s13167-020-00217-y. PubMed DOI PMC

Liskova A, Samec M, Koklesova L, Kudela E, Kubatka P, Golubnitschaja O. Mitochondriopathies as a clue to systemic disorders—analytical tools and mitigating measures in context of predictive, preventive, and personalized (3P) Medicine. Int J Mol Sci 2021;22, 10.3390/ijms22042007. PubMed PMC

Koklesova L, Samec M, Liskova A, Zhai K, Büsselberg D, Giordano FA, et al. Mitochondrial impairments in aetiopathology of multifactorial diseases: common origin but individual outcomes in context of 3P medicine. EPMA J. 2021;1–14, 10.1007/s13167-021-00237-2. PubMed PMC

Solnier J, Fladerer J-P. Flavonoids: A complementary approach to conventional therapy of COVID-19? Phytochem Rev. 2020;1–23, 10.1007/s11101-020-09720-6. PubMed PMC

Liskova A, Samec M, Koklesova L, Samuel SM, Zhai K, Al-Ishaq RK, et al. Flavonoids against the SARS-CoV-2 induced inflammatory storm. Biomed Pharmacother. 2021;138:111430. doi: 10.1016/j.biopha.2021.111430. PubMed DOI PMC

Crigna AT, Samec M, Koklesova L, Liskova A, Giordano FA, Kubatka P, et al. Cell-free nucleic acid patterns in disease prediction and monitoring-hype or hope? EPMA J. 2020;1–25, 10.1007/s13167-020-00226-x. PubMed PMC

Falzone L, Salomone S, Libra M. Evolution of cancer pharmacological treatments at the turn of the third millennium. Front Pharmacol 2018;9, 10.3389/fphar.2018.01300. PubMed PMC

Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12:237–251. doi: 10.1038/nrc3237. PubMed DOI PMC

Chen HHW, Kuo MT. Improving radiotherapy in cancer treatment: Promises and challenges. Oncotarget. 2017;8:62742–62758. doi: 10.18632/oncotarget.18409. PubMed DOI PMC

Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci 2020;21, 10.3390/ijms21093233. PubMed PMC

Koukourakis MI, Giatromanolaki A. Warburg effect, lactate dehydrogenase, and radio/chemo-therapy efficacy. Int J Radiat Biol. 2019;95:408–426. doi: 10.1080/09553002.2018.1490041. PubMed DOI

Baudino TA. Targeted cancer therapy: the next generation of cancer treatment. Curr Drug Discov Technol. 2015;12:3–20. doi: 10.2174/1570163812666150602144310. PubMed DOI

Inthagard J, Edwards J, Roseweir AK. Immunotherapy: enhancing the efficacy of this promising therapeutic in multiple cancers. Clin Sci (Lond) 2019;133:181–193. doi: 10.1042/CS20181003. PubMed DOI

Pan S-T, Li Z-L, He Z-X, Qiu J-X, Zhou S-F. Molecular mechanisms for tumour resistance to chemotherapy. Clin Exp Pharmacol Physiol. 2016;43:723–737. doi: 10.1111/1440-1681.12581. PubMed DOI

Wang X, Zhang H, Chen X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resistance. 2019;2:141–160. doi: 10.20517/cdr.2019.10. PubMed DOI PMC

Liskova A, Samec M, Koklesova L, Giordano FA, Kubatka P, Golubnitschaja O. Liquid Biopsy is Instrumental for 3PM Dimensional Solutions in Cancer Management. Journal of Clinical Medicine. Multidisciplinary Digital Publishing Institute; 2020;9:2749, 10.3390/jcm9092749. PubMed PMC

Grech G, Zhan X, Yoo BC, Bubnov R, Hagan S, Danesi R, et al. EPMA position paper in cancer: current overview and future perspectives. EPMA J. 2015;6:9. doi: 10.1186/s13167-015-0030-6. PubMed DOI PMC

Kapinova A, Kubatka P, Liskova A, Baranenko D, Kruzliak P, Matta M, et al. Controlling metastatic cancer: the role of phytochemicals in cell signaling. J Cancer Res Clin Oncol. 2019;145:1087–1109. doi: 10.1007/s00432-019-02892-5. PubMed DOI

Kapinova A, Kubatka P, Golubnitschaja O, Kello M, Zubor P, Solar P, et al. Dietary phytochemicals in breast cancer research: anticancer effects and potential utility for effective chemoprevention. Environ Health Prev Med. 2018;23:36. doi: 10.1186/s12199-018-0724-1. PubMed DOI PMC

Kubatka P, Kello M, Kajo K, Kruzliak P, Výbohová D, Šmejkal K, et al. Young Barley Indicates Antitumor Effects in Experimental Breast Cancer In Vivo and In Vitro. Nutr Cancer. 2016;68:611–621. doi: 10.1080/01635581.2016.1154577. PubMed DOI

Kubatka P, Kapinová A, Kello M, Kruzliak P, Kajo K, Výbohová D, et al. Fruit peel polyphenols demonstrate substantial anti-tumour effects in the model of breast cancer. Eur J Nutr. 2016;55:955–965. doi: 10.1007/s00394-015-0910-5. PubMed DOI

Kubatka P, Uramova S, Kello M, Kajo K, Samec M, Jasek K, et al. Anticancer Activities of Thymus vulgaris L. in Experimental Breast Carcinoma in Vivo and in Vitro. Int J Mol Sci. 2019;20, 10.3390/ijms20071749. PubMed PMC

Kubatka P, Kello M, Kajo K, Samec M, Jasek K, Vybohova D, et al. Chemopreventive and Therapeutic Efficacy of Cinnamomum zeylanicum L. Bark in Experimental Breast Carcinoma: Mechanistic In Vivo and In Vitro Analyses. Molecules. 2020;25:1399. doi: 10.3390/molecules25061399. PubMed DOI PMC

Kubatka P, Kello M, Kajo K, Samec M, Liskova A, Jasek K, et al. Rhus coriaria L. (Sumac) Demonstrates Oncostatic Activity in the Therapeutic and Preventive Model of Breast Carcinoma. Int J Mol Sci. 2020;22, 10.3390/ijms22010183. PubMed PMC

Koklesova L, Liskova A, Samec M, Buhrmann C, Samuel SM, Varghese E, et al. Carotenoids in cancer apoptosis-the road from bench to bedside and back. Cancers (Basel). 2020;12, 10.3390/cancers12092425. PubMed PMC

Kubatka P, Kello M, Kajo K, Kruzliak P, Výbohová D, Mojžiš J, et al. Oregano demonstrates distinct tumour-suppressive effects in the breast carcinoma model. Eur J Nutr. 2017;56:1303–1316. doi: 10.1007/s00394-016-1181-5. PubMed DOI

Kubatka P, Uramova S, Kello M, Kajo K, Kruzliak P, Mojzis J, et al. Antineoplastic effects of clove buds (Syzygium aromaticum L) in the model of breast carcinoma. J Cell Mol Med. 2017;21:2837–51. doi: 10.1111/jcmm.13197. PubMed DOI PMC

Ashrafizadeh M, Ahmadi Z, Farkhondeh T, Samarghandian S. Resveratrol targeting the Wnt signaling pathway: A focus on therapeutic activities. J Cell Physiol. 2020;235:4135–4145. doi: 10.1002/jcp.29327. PubMed DOI

Ashrafizadeh M, Tavakol S, Ahmadi Z, Roomiani S, Mohammadinejad R, Samarghandian S. Therapeutic effects of kaempferol affecting autophagy and endoplasmic reticulum stress. Phytother Res. 2020;34:911–923. doi: 10.1002/ptr.6577. PubMed DOI

Ashrafizadeh M, Rafiei H, Mohammadinejad R, Afshar EG, Farkhondeh T, Samarghandian S. Potential therapeutic effects of curcumin mediated by JAK/STAT signaling pathway: A review. Phytother Res. 2020;34:1745–1760. doi: 10.1002/ptr.6642. PubMed DOI

Ashrafizadeh M, Ahmadi Z, Farkhondeh T, Samarghandian S. Autophagy regulation using luteolin: new insight into its anti-tumor activity. Cancer Cell Int. 2020;20:537. doi: 10.1186/s12935-020-01634-9. PubMed DOI PMC

Ashrafizadeh M, Ahmadi Z, Mohammadinejad R, Ghasemipour Afshar E. Tangeretin: a mechanistic review of its pharmacological and therapeutic effects. J Basic Clin Physiol Pharmacol. 2020;31, 10.1515/jbcpp-2019-0191. PubMed

Buhrmann C, Shayan P, Brockmueller A, Shakibaei M. Resveratrol suppresses cross-talk between colorectal cancer cells and stromal cells in multicellular tumor microenvironment: a bridge between in vitro and in vivo tumor microenvironment study. Molecules. 2020;25, 10.3390/molecules25184292. PubMed PMC

Buhrmann C, Popper B, Kunnumakkara AB, Aggarwal BB, Shakibaei M. Evidence that calebin a, a component of curcuma longa suppresses NF-B mediated proliferation, invasion and metastasis of human colorectal cancer induced by TNF-β (Lymphotoxin). Nutrients. 2019;11, 10.3390/nu11122904. PubMed PMC

Bhia M, Motallebi M, Abadi B, Zarepour A, Pereira-Silva M, Saremnejad F, et al. Naringenin nano-delivery systems and their therapeutic applications. Pharmaceutics. 2021;13, 10.3390/pharmaceutics13020291. PubMed PMC

Zhai K, Brockmüller A, Kubatka P, Shakibaei M, Büsselberg D. Curcumin’s beneficial effects on neuroblastoma: mechanisms, challenges, and potential solutions. Biomolecules. 2020;10, 10.3390/biom10111469. PubMed PMC

Abotaleb M, Liskova A, Kubatka P, Büsselberg D. Therapeutic potential of plant phenolic acids in the treatment of cancer. Biomolecules. 2020;10, doi:10.3390/biom10020221. PubMed PMC

Varghese E, Samuel SM, Abotaleb M, Cheema S, Mamtani R, Büsselberg D. The “Yin and Yang” of natural compounds in anticancer therapy of triple-negative breast cancers. Cancers (Basel). 2018;10, 10.3390/cancers10100346. PubMed PMC

Liskova A, Kubatka P, Samec M, Zubor P, Mlyncek M, Bielik T, et al. Dietary Phytochemicals Targeting Cancer Stem Cells. Molecules 2019;24, 10.3390/molecules24050899. PubMed PMC

Riganti C, Contino M. New Strategies to overcome resistance to chemotherapy and immune system in cancer. Int J Mol Sci 2019; 20, 10.3390/ijms20194783. PubMed PMC

Pintova S, Dharmupari S, Moshier E, Zubizarreta N, Ang C, Holcombe RF. Genistein combined with FOLFOX or FOLFOX-Bevacizumab for the treatment of metastatic colorectal cancer: phase I/II pilot study. Cancer Chemother Pharmacol. 2019;84:591–598. doi: 10.1007/s00280-019-03886-3. PubMed DOI

Lazzeroni M, Guerrieri-Gonzaga A, Gandini S, Johansson H, Serrano D, Cazzaniga M, et al. A presurgical study of lecithin formulation of green tea extract in women with early breast cancer. Cancer Prev Res (Phila) 2017;10:363–370. doi: 10.1158/1940-6207.CAPR-16-0298. PubMed DOI

Farsad-Naeimi A, Alizadeh M, Esfahani A, Darvish AE. Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients. Food Funct. 2018;9:2025–2031. doi: 10.1039/c7fo01898c. PubMed DOI

Liskova A, Koklesova L, Samec M, Smejkal K, Samuel SM, Varghese E, et al. Flavonoids in Cancer Metastasis. Cancers (Basel). 2020;12, 10.3390/cancers12061498. PubMed PMC

Liskova A, Koklesova L, Samec M, Varghese E, Abotaleb M, Samuel SM, et al. Implications of flavonoids as potential modulators of cancer neovascularity. J Cancer Res Clin Oncol. 2020 doi: 10.1007/s00432-020-03383-8. PubMed DOI

Tang Q, Ma J, Sun J, Yang L, Yang F, Zhang W, et al. Genistein and AG1024 synergistically increase the radiosensitivity of prostate cancer cells. Oncol Rep. 2018;40:579–588. doi: 10.3892/or.2018.6468. PubMed DOI PMC

Koh SY, Moon JY, Unno T, Cho SK. Baicalein Suppresses Stem Cell-Like Characteristics in Radio- and Chemoresistant MDA-MB-231 Human Breast Cancer Cells through Up-Regulation of IFIT2. Nutrients 2019;11, 10.3390/nu11030624. PubMed PMC

Li S, Zhao Q, Wang B, Yuan S, Wang X, Li K. Quercetin reversed MDR in breast cancer cells through down-regulating P-gp expression and eliminating cancer stem cells mediated by YB-1 nuclear translocation. Phytother Res. 2018;32:1530–1536. doi: 10.1002/ptr.6081. PubMed DOI

Singh MP, Cho HJ, Kim J-T, Baek KE, Lee HG, Kang SC. Morin hydrate reverses cisplatin resistance by impairing PARP1/HMGB1-dependent autophagy in hepatocellular carcinoma. Cancers (Basel) 2019;11, 10.3390/cancers11070986. PubMed PMC

Riahi-Chebbi I, Souid S, Othman H, Haoues M, Karoui H, Morel A, et al. The Phenolic compound Kaempferol overcomes 5-fluorouracil resistance in human resistant LS174 colon cancer cells. Sci Rep. 2019;9:195. doi: 10.1038/s41598-018-36808-z. PubMed DOI PMC

Moradzadeh M, Tabarraei A, Sadeghnia HR, Ghorbani A, Mohamadkhani A, Erfanian S, et al. Kaempferol increases apoptosis in human acute promyelocytic leukemia cells and inhibits multidrug resistance genes. J Cell Biochem. 2018;119:2288–2297. doi: 10.1002/jcb.26391. PubMed DOI

Bae S, D’Cunha R, Shao J, An G. Effect of 5,7-dimethoxyflavone on Bcrp1-mediated transport of sorafenib in vitro and in vivo in mice. Eur J Pharm Sci. 2018;117:27–34. doi: 10.1016/j.ejps.2018.02.004. PubMed DOI

Leu Y-L, Wang T-H, Wu C-C, Huang K-Y, Jiang Y-W, Hsu Y-C, et al. Hydroxygenkwanin suppresses non-small cell lung cancer progression by enhancing EGFR degradation. Molecules 2020;25, 10.3390/molecules25040941. PubMed PMC

Chen Z, Tian D, Liao X, Zhang Y, Xiao J, Chen W, et al. Apigenin combined with gefitinib blocks autophagy flux and induces apoptotic cell death through inhibition of HIF-1α, c-Myc, p-EGFR, and glucose metabolism in EGFR L858R+T790M-Mutated H1975 Cells. Front Pharmacol. 2019;10:260. doi: 10.3389/fphar.2019.00260. PubMed DOI PMC

Sellam LS, Zappasodi R, Chettibi F, Djennaoui D, Yahi-Ait Mesbah N, Amir-Tidadini Z-C, et al. Silibinin down-regulates PD-L1 expression in nasopharyngeal carcinoma by interfering with tumor cell glycolytic metabolism. Arch Biochem Biophys. 2020;690:108479. doi: 10.1016/j.abb.2020.108479. PubMed DOI PMC

Bailly C. Molecular and cellular basis of the anticancer activity of the prenylated flavonoid icaritin in hepatocellular carcinoma. Chem Biol Interact. 2020;325:109124. doi: 10.1016/j.cbi.2020.109124. PubMed DOI

Tang H, Liu Y, Wang C, Zheng H, Chen Y, Liu W, et al. Inhibition of COX-2 and EGFR by Melafolone Improves Anti-PD-1 Therapy through Vascular Normalization and PD-L1 Downregulation in Lung Cancer. J Pharmacol Exp Ther. 2019;368:401–413. doi: 10.1124/jpet.118.254359. PubMed DOI

Nikolaou M, Pavlopoulou A, Georgakilas AG, Kyrodimos E. The challenge of drug resistance in cancer treatment: a current overview. Clin Exp Metastasis. 2018;35:309–318. doi: 10.1007/s10585-018-9903-0. PubMed DOI

Golubnitschaja O, Polivka J, Yeghiazaryan K, Berliner L. Liquid biopsy and multiparametric analysis in management of liver malignancies: new concepts of the patient stratification and prognostic approach. EPMA J. 2018;9:271–285. doi: 10.1007/s13167-018-0146-6. PubMed DOI PMC

Gerner C, Costigliola V, Golubnitschaja O. Multiomic patterns in body fluids: technological challenge with a great potential to implement the advanced paradigm of 3P medicine. Mass Spectrom Rev. 2020;39:442–451. doi: 10.1002/mas.21612. PubMed DOI

Fröhlich H, Patjoshi S, Yeghiazaryan K, Kehrer C, Kuhn W, Golubnitschaja O. Premenopausal breast cancer: potential clinical utility of a multi-omics based machine learning approach for patient stratification. EPMA J. 2018;9:175–186. doi: 10.1007/s13167-018-0131-0. PubMed DOI PMC

Golubnitschaja O. Feeling cold and other underestimated symptoms in breast cancer: anecdotes or individual profiles for advanced patient stratification? EPMA J. 2017;8:17–22. doi: 10.1007/s13167-017-0086-6. PubMed DOI PMC

Goldstein E, Yeghiazaryan K, Ahmad A, Giordano FA, Fröhlich H, Golubnitschaja O. Optimal multiparametric set-up modelled for best survival outcomes in palliative treatment of liver malignancies: unsupervised machine learning and 3 PM recommendations. EPMA J. 2020;1–11, 10.1007/s13167-020-00221-2. PubMed PMC

Golubnitschaja O, editor. Flammer syndrome: from phenotype to associated pathologies, prediction, prevention and personalisation advances in predictive, preventive and personalised medicine; Springer International Publishing, 2019; ISBN 978–3–030–13549–2, 10.1007/978-3-030-13550-8.

Ye Q, Liu K, Shen Q, Li Q, Hao J, Han F, et al. Reversal of Multidrug resistance in cancer by multi-functional flavonoids. Front Oncol 2019;9, 10.3389/fonc.2019.00487. PubMed PMC

Wong ILK, Zhu X, Chan K-F, Law MC, Lo AMY, Hu X, et al. Discovery of Novel Flavonoid Dimers To Reverse Multidrug Resistance Protein 1 (MRP1, ABCC1) Mediated Drug Resistance in Cancers Using a High Throughput Platform with “Click Chemistry”. J Med Chem. 2018;61:9931–9951. doi: 10.1021/acs.jmedchem.8b00834. PubMed DOI

Namdeo AG, Boddu SHS, Amawi H, Ashby CR, Tukaramrao DB, Trivedi P, et al. Flavonoids as Multi-Target Compounds: A Special Emphasis on their Potential as Chemo-adjuvants in Cancer Therapy. Curr Pharm Des. 2020;26:1712–1728. doi: 10.2174/1381612826666200128095248. PubMed DOI

Hussain Y, Luqman S, Meena A. Research progress in flavonoids as potential anticancer drug including synergy with other approaches. Curr Top Med Chem. 2020;20:1791–1809. doi: 10.2174/1568026620666200502005411. PubMed DOI

Abotaleb M, Samuel SM, Varghese E, Varghese S, Kubatka P, Liskova A, et al. Flavonoids in Cancer and Apoptosis. Cancers (Basel) 2018;11, 10.3390/cancers11010028. PubMed PMC

Samec M, Liskova A, Koklesova L, Mersakova S, Strnadel J, Kajo K, et al. Flavonoids Targeting HIF-1: Implications on Cancer Metabolism. Cancers. 2021;13:130. doi: 10.3390/cancers13010130. PubMed DOI PMC

Lv W-L, Liu Q, An J-H, Song X-Y. Scutellarin inhibits hypoxia-induced epithelial-mesenchymal transition in bladder cancer cells. J Cell Physiol. 2019;234:23169–23175. doi: 10.1002/jcp.28883. PubMed DOI

Hsiao Y-H, Hsieh M-J, Yang S-F, Chen S-P, Tsai W-C, Chen P-N. Phloretin suppresses metastasis by targeting protease and inhibits cancer stemness and angiogenesis in human cervical cancer cells. Phytomedicine. 2019;62:152964. doi: 10.1016/j.phymed.2019.152964. PubMed DOI

Jiang C-H, Sun T-L, Xiang D-X, Wei S-S, Li W-Q. Anticancer activity and mechanism of xanthohumol: a prenylated flavonoid from hops (Humulus lupulus L.). Front Pharmacol 2018;9, 10.3389/fphar.2018.00530. PubMed PMC

Kozłowska A, Szostak-Wegierek D. Flavonoids–food sources and health benefits. Rocz Panstw Zakl Hig. 2014;65:79–85. PubMed

Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. ScientificWorldJournal 2013;2013, 10.1155/2013/162750. PubMed PMC

Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci 2016;5, 10.1017/jns.2016.41. PubMed PMC

Al-Ishaq RK, Abotaleb M, Kubatka P, Kajo K, Büsselberg D. Flavonoids and their anti-diabetic effects: cellular mechanisms and effects to improve blood sugar levels. Biomolecules. 2019;9, 10.3390/biom9090430. PubMed PMC

Pichler C, Ferk F, Al-Serori H, Huber W, Jäger W, Waldherr M, et al. Xanthohumol Prevents DNA Damage by Dietary Carcinogens: Results of a Human Intervention Trial. Cancer Prev Res (Phila) 2017;10:153–160. doi: 10.1158/1940-6207.CAPR-15-0378. PubMed DOI

Lievens Y, Borras JM, Grau C. Provision and use of radiotherapy in Europe. Mol Oncol. 2020;14:1461–1469. doi: 10.1002/1878-0261.12690. PubMed DOI PMC

Taguchi K, Yamamoto M. The KEAP1-NRF2 System in Cancer. Front Oncol. 2017;7:85. doi: 10.3389/fonc.2017.00085. PubMed DOI PMC

Liu X, Sun C, Liu B, Jin X, Li P, Zheng X, et al. Genistein mediates the selective radiosensitizing effect in NSCLC A549 cells via inhibiting methylation of the keap1 gene promoter region. Oncotarget. 2016;7:27267–27279. doi: 10.18632/oncotarget.8403. PubMed DOI PMC

Takahashi A, Kubo M, Ma H, Nakagawa A, Yoshida Y, Isono M, et al. Nonhomologous End-Joining Repair Plays a More Important Role than Homologous Recombination Repair in Defining Radiosensitivity after Exposure to High-LET Radiation. Radiat Res. 2014;182:338–344. doi: 10.1667/RR13782.1. PubMed DOI

Tiwari P, Mishra KP. Flavonoids sensitize tumor cells to radiation: molecular mechanisms and relevance to cancer radiotherapy. Int J Radiat Biol. 2020;96:360–369. doi: 10.1080/09553002.2020.1694193. PubMed DOI

Zhang Z, Jin F, Lian X, Li M, Wang G, Lan B, et al. Genistein promotes ionizing radiation-induced cell death by reducing cytoplasmic Bcl-xL levels in non-small cell lung cancer. Sci Rep. 2018;8:328. 10.1038/s41598-017-18755-3. PubMed PMC

Medhat AM, Azab KS, Said MM, El Fatih NM, El Bakary NM. Antitumor and radiosensitizing synergistic effects of apigenin and cryptotanshinone against solid Ehrlich carcinoma in female mice. Tumour Biol. 2017;39:1010428317728480. doi: 10.1177/1010428317728480. PubMed DOI

Abdraboh ME, Essa ZS, Abdelrazzak AB, El-Far YM, Elsherbini Y, El-Zayat MM, et al. Radio-sensitizing effect of a cocktail of phytochemicals on HepG2 cell proliferation, motility and survival. Biomed Pharmacother. 2020;131:110620. doi: 10.1016/j.biopha.2020.110620. PubMed DOI

Li Y, Wang Z, Jin J, Zhu S-X, He G-Q, Li S-H, et al. Quercetin pretreatment enhances the radiosensitivity of colon cancer cells by targeting Notch-1 pathway. Biochem Biophys Res Commun. 2020;523:947–953. doi: 10.1016/j.bbrc.2020.01.048. PubMed DOI

Ma L, Zong X. Metabolic Symbiosis in Chemoresistance: Refocusing the Role of Aerobic Glycolysis. Front Oncol 2020;10, 10.3389/fonc.2020.00005. PubMed PMC

Wilkens S. Structure and mechanism of ABC transporters. F1000Prime Rep 2015;7, 10.12703/P7-14. PubMed PMC

Begicevic R-R, Falasca M. ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance. Int J Mol Sci 2017;18, 10.3390/ijms18112362. PubMed PMC

Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, et al. Drug Resistance in Cancer: An Overview. Cancers (Basel) 2014;6:1769–1792. doi: 10.3390/cancers6031769. PubMed DOI PMC

Januchowski R, Wojtowicz K, Zabel M. The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance. Biomed Pharmacother. 2013;67:669–680. doi: 10.1016/j.biopha.2013.04.005. PubMed DOI

Sakthivel KM, Hariharan S. Regulatory players of DNA damage repair mechanisms: Role in Cancer Chemoresistance. Biomed Pharmacother. 2017;93:1238–1245. doi: 10.1016/j.biopha.2017.07.035. PubMed DOI

Salehan MR, Morse HR. DNA damage repair and tolerance: a role in chemotherapeutic drug resistance. Br J Biomed Sci. 2013;70:31–40. doi: 10.1080/09674845.2013.11669927. PubMed DOI

Liu R, Chen Y, Liu G, Li C, Song Y, Cao Z, et al. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis 2020;11, 10.1038/s41419-020-02998-6. PubMed PMC

Lu X, Yang F, Chen D, Zhao Q, Chen D, Ping H, et al. Quercetin reverses docetaxel resistance in prostate cancer via androgen receptor and PI3K/Akt signaling pathways. Int J Biol Sci. 2020;16:1121–1134. doi: 10.7150/ijbs.41686. PubMed DOI PMC

Choi HJ, Heo JH, Park JY, Jeong JY, Cho HJ, Park KS, et al. A novel PI3K/mTOR dual inhibitor, CMG002, overcomes the chemoresistance in ovarian cancer. Gynecol Oncol. 2019;153:135–148. doi: 10.1016/j.ygyno.2019.01.012. PubMed DOI

Cho Y, Kim YK. Cancer Stem Cells as a Potential Target to Overcome Multidrug Resistance. Front Oncol 2020;10, 10.3389/fonc.2020.00764. PubMed PMC

Bahar E, Kim J-Y, Yoon H. Chemotherapy Resistance Explained through Endoplasmic Reticulum Stress-Dependent Signaling. Cancers (Basel) 2019, 11, doi:10.3390/cancers11030338. PubMed PMC

Kim E-K, Jang M, Song M-J, Kim D, Kim Y, Jang HH. Redox-mediated mechanism of chemoresistance in cancer cells. Antioxidants (Basel). 2019;8, 10.3390/antiox8100471. PubMed PMC

Lan C-Y, Chen S-Y, Kuo C-W, Lu C-C, Yen G-C. Quercetin facilitates cell death and chemosensitivity through RAGE/PI3K/AKT/mTOR axis in human pancreatic cancer cells. J Food Drug Anal. 2019;27:887–896. doi: 10.1016/j.jfda.2019.07.001. PubMed DOI PMC

Hassanzadeh P. Colorectal cancer and NF-κB signaling pathway. Gastroenterol Hepatol Bed Bench. 2011;4:127–32, PMC4017424. PubMed PMC

Liu S, Li R, Qian J, Sun J, Li G, Shen J, et al. Combination therapy of doxorubicin and quercetin on multidrug-resistant breast cancer and their sequential delivery by reduction-sensitive hyaluronic acid-based conjugate/d-α-Tocopheryl Poly(ethylene glycol) 1000 succinate mixed micelles. Mol Pharm. 2020;17:1415–1427. doi: 10.1021/acs.molpharmaceut.0c00138. PubMed DOI

Bieg D, Sypniewski D, Nowak E, Bednarek I. Morin decreases galectin-3 expression and sensitizes ovarian cancer cells to cisplatin. Arch Gynecol Obstet. 2018;298:1181–1194. doi: 10.1007/s00404-018-4912-4. PubMed DOI PMC

Zhang X, Huang J, Yu C, Xiang L, Li L, Shi D, et al. Quercetin Enhanced Paclitaxel Therapeutic Effects Towards PC-3 Prostate Cancer Through ER Stress Induction and ROS Production. Onco Targets Ther. 2020;13:513–523. doi: 10.2147/OTT.S228453. PubMed DOI PMC

Silbermann K, Shah CP, Sahu NU, Juvale K, Stefan SM, Kharkar PS, et al. Novel chalcone and flavone derivatives as selective and dual inhibitors of the transport proteins ABCB1 and ABCG2. Eur J Med Chem. 2019;164:193–213. doi: 10.1016/j.ejmech.2018.12.019. PubMed DOI

Kong W, Ling X, Chen Y, Wu X, Zhao Z, Wang W, et al. Hesperetin reverses P-glycoprotein-mediated cisplatin resistance in DDP-resistant human lung cancer cells via modulation of the nuclear factor-κB signaling pathway. Int J Mol Med. 2020;45:1213–1224. doi: 10.3892/ijmm.2020.4485. PubMed DOI PMC

Zhao L, Zhang W, Zhang F. Poncirin downregulates ATP-binding cassette transporters to enhance cisplatin sensitivity in cisplatin-resistant osteosarcoma cells. Phytother Res. 2021;35:278–288. doi: 10.1002/ptr.6798. PubMed DOI

Scagliarini A, Mathey A, Aires V, Delmas D. Xanthohumol, a Prenylated Flavonoid from Hops, Induces DNA Damages in Colorectal Cancer Cells and Sensitizes SW480 Cells to the SN38 Chemotherapeutic Agent. Cells. 2020;9, 10.3390/cells9040932. PubMed PMC

Hua R, Pei Y, Gu H, Sun Y, He Y. Antitumor effects of flavokawain-B flavonoid in gemcitabine-resistant lung cancer cells are mediated via mitochondrial-mediated apoptosis, ROS production, cell migration and cell invasion inhibition and blocking of PI3K/AKT Signaling pathway. J BUON. 2020;25:262–267. PubMed

Fan X, Bai J, Zhao S, Hu M, Sun Y, Wang B, et al. Evaluation of inhibitory effects of flavonoids on breast cancer resistance protein (BCRP): From library screening to biological evaluation to structure-activity relationship. Toxicol In Vitro. 2019;61:104642. doi: 10.1016/j.tiv.2019.104642. PubMed DOI

Wang Z, Sun X, Feng Y, Wang Y, Zhang L, Wang Y, et al. Dihydromyricetin reverses MRP2-induced multidrug resistance by preventing NF-κB-Nrf2 signaling in colorectal cancer cell. Phytomedicine. 2021;82:153414. doi: 10.1016/j.phymed.2020.153414. PubMed DOI

Darzi S, Mirzaei SA, Elahian F, Shirian S, Peymani A, Rahmani B, et al. Enhancing the Therapeutic Efficacy of Daunorubicin and Mitoxantrone with Bavachinin, Candidone, and Tephrosin. Evid Based Complement Alternat Med. 2019;2019:3291737. doi: 10.1155/2019/3291737. PubMed DOI PMC

Khonkarn R, Daowtak K, Okonogi S. Chemotherapeutic Efficacy Enhancement in P-gp-Overexpressing Cancer Cells by Flavonoid-Loaded Polymeric Micelles. AAPS PharmSciTech. 2020;21:121. doi: 10.1208/s12249-020-01657-5. PubMed DOI

Jabri T, Imran M, Aziz A, Rao K, Kawish M, Irfan M, et al. Design and synthesis of mixed micellar system for enhanced anticancer efficacy of Paclitaxel through its co-delivery with Naringin. Drug Dev Ind Pharm. 2019;45:703–714. doi: 10.1080/03639045.2018.1550091. PubMed DOI

Wang B, Guo C, Liu Y, Han G, Li Y, Zhang Y, et al. Novel nano-pomegranates based on astragalus polysaccharides for targeting ERα-positive breast cancer and multidrug resistance. Drug Deliv. 2020;27:607–621. doi: 10.1080/10717544.2020.1754529. PubMed DOI PMC

Wen M, Xia J, Sun Y, Wang X, Fu X, Zhang Y, et al. Combination of EGFR-TKIs with chemotherapy versus chemotherapy or EGFR-TKIs alone in advanced NSCLC patients with EGFR mutation. Biologics. 2018;12:183–190. doi: 10.2147/BTT.S169305. PubMed DOI PMC

Karachaliou N, Gonzalez-Cao M, Sosa A, Berenguer J, Bracht JWP, Ito M, et al. The combination of checkpoint immunotherapy and targeted therapy in cancer. Ann Transl Med 2017;5, 10.21037/atm.2017.06.47. PubMed PMC

Wang H, Pan R, Zhang X, Si X, Wang M, Zhang L. Abivertinib in patients with T790M-positive advanced NSCLC and its subsequent treatment with osimertinib. Thorac Cancer. 2020;11:594–602. doi: 10.1111/1759-7714.13302. PubMed DOI PMC

Huang S, Yu M, Shi N, Zhou Y, Li F, Li X, et al. Apigenin and Abivertinib, a novel BTK inhibitor synergize to inhibit diffuse large B-cell lymphoma in vivo and vitro. J Cancer. 2020;11:2123–2132. doi: 10.7150/jca.34981. PubMed DOI PMC

Harrison PT, Huang PH. Exploiting vulnerabilities in cancer signalling networks to combat targeted therapy resistance. Essays Biochem. 2018;62:583–593. doi: 10.1042/EBC20180016. PubMed DOI PMC

Sambi M, Szewczuk MR. Introduction to the Acquisition of Resistance to Targeted Therapy. In: Szewczuk MR, Qorri B, Sambi M, editors. Current Applications for Overcoming Resistance to Targeted Therapies, Springer International Publishing: Cham, 2019; pp. 1–33 ISBN 978–3–030–21477–7, 10.1007/978-3-030-21477-7_1.

Sabnis AJ, Bivona TG. Principles of Resistance to Targeted Cancer Therapy: Lessons from Basic and Translational Cancer Biology. Trends in Molecular Medicine. Elsevier; 2019;25:185–97, 10.1016/j.molmed.2018.12.009. PubMed PMC

Groenendijk FH, Bernards R. Drug resistance to targeted therapies: Déjà vu all over again. Mol Oncol. 2014;8:1067–1083. doi: 10.1016/j.molonc.2014.05.004. PubMed DOI PMC

Chen D-H, Zhang X-S. Targeted therapy: resistance and re-sensitization. Chin J Cancer 2015;34, 10.1186/s40880-015-0047-1. PubMed PMC

Li X, Xu J, Tang X, Liu Y, Yu X, Wang Z, et al. Anthocyanins inhibit trastuzumab-resistant breast cancer in vitro and in vivo. Mol Med Rep. 2016;13:4007–4013. doi: 10.3892/mmr.2016.4990. PubMed DOI

Zhang L, Qi Y, Xing K, Qian S, Zhang P, Wu X. A novel strategy of EGFR‑TKI combined chemotherapy in the treatment of human lung cancer with EGFR‑sensitive mutation. Oncology Reports. Spandidos Publications; 2018;40:1046–54, 10.3892/or.2018.6499. PubMed

Sim EH, Yang IA, Wood-Baker R, Bowman RV, Fong KM. Gefitinib for advanced non-small cell lung cancer. Cochrane Database Syst Rev. 2018;1:CD006847. doi: 10.1002/14651858.CD006847.pub2. PubMed DOI PMC

Wu Z, Xu B, Yu Z, He Q, Hu Z, Zhou S, et al. Trifolium Flavonoids Overcome Gefitinib Resistance of Non-Small-Cell Lung Cancer Cell by Suppressing ERK and STAT3 Signaling Pathways. Biomed Res Int. 2020;2020:2491304. doi: 10.1155/2020/2491304. PubMed DOI PMC

Liu J, Zhong T, Yi P, Fan C, Zhang Z, Liang G, et al. A new epigallocatechin gallate derivative isolated from Anhua dark tea sensitizes the chemosensitivity of gefitinib via the suppression of PI3K/mTOR and epithelial-mesenchymal transition. Fitoterapia. 2020;143:104590. doi: 10.1016/j.fitote.2020.104590. PubMed DOI

Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduction and Targeted Therapy. Nature Publishing Group; 2020;5:1–15, 10.1038/s41392-020-0187-x. PubMed PMC

Li B, Feng F, Jia H, Jiang Q, Cao S, Wei L, et al. Rhamnetin decelerates the elimination and enhances the antitumor effect of the molecular-targeting agent sorafenib in hepatocellular carcinoma cells via the miR-148a/PXR axis. Food Funct. 2021 doi: 10.1039/d0fo02270e. PubMed DOI

Şirin N, Elmas L, Seçme M, Dodurga Y. Investigation of possible effects of apigenin, sorafenib and combined applications on apoptosis and cell cycle in hepatocellular cancer cells. Gene. 2020;737:144428. doi: 10.1016/j.gene.2020.144428. PubMed DOI

Saraswati S, Alhaider A, Abdelgadir AM, Tanwer P, Korashy HM. Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1-mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma. Cell Commun Signal. 2019;17:127. doi: 10.1186/s12964-019-0430-7. PubMed DOI PMC

Nair B, Anto RJ, M S, Nath LR. Kaempferol-Mediated Sensitization Enhances Chemotherapeutic Efficacy of Sorafenib Against Hepatocellular Carcinoma: An In Silico and In Vitro Approach. Adv Pharm Bull. 2020;10:472–6, 10.34172/apb.2020.058. PubMed PMC

Yeh B-W, Yu L-E, Li C-C, Yang J-C, Li W-M, Wu Y-C, et al. The protoapigenone analog WYC0209 targets CD133+ cells: A potential adjuvant agent against cancer stem cells in urothelial cancer therapy. Toxicol Appl Pharmacol. 2020;402:115129. doi: 10.1016/j.taap.2020.115129. PubMed DOI

Li L, Zheng Y, Zhang W, Hou L, Gao Y. Scutellarin circumvents chemoresistance, promotes apoptosis, and represses tumor growth by HDAC/miR-34a-mediated down-modulation of Akt/mTOR and NF-κB-orchestrated signaling pathways in multiple myeloma. Int J Clin Exp Pathol. 2020;13:212–9. PMC7061792. PubMed PMC

Kim B, Seo JH, Lee KY, Park B. Icariin sensitizes human colon cancer cells to TRAIL-induced apoptosis via ERK-mediated upregulation of death receptors. Int J Oncol. 2020;56:821–834. doi: 10.3892/ijo.2020.4970. PubMed DOI

Liu Y-S, Yu-Chun, Chang, Kuo W-W, Chen M-C, Hsu H-H, et al. Inhibition of protein phosphatase 1 stimulates noncanonical ER stress eIF2α activation to enhance fisetin-induced chemosensitivity in HDAC inhibitor-resistant hepatocellular carcinoma cells. Cancers (Basel). 2019;11, 10.3390/cancers11070918. PubMed PMC

Suraweera A, O’Byrne KJ, Richard DJ. Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi. Front Oncol 2018;8, 10.3389/fonc.2018.00092. PubMed PMC

Thapa B, Kc R, Uludağ H. TRAIL therapy and prospective developments for cancer treatment. J Control Release. 2020;326:335–349. doi: 10.1016/j.jconrel.2020.07.013. PubMed DOI

Wang F, Lin J, Xu R. The molecular mechanisms of TRAIL resistance in cancer cells: help in designing new drugs. Curr Pharm Des. 2014;20:6714–6722. doi: 10.2174/1381612820666140929100735. PubMed DOI

Guo S, Zhang Y, Wu Z, Zhang L, He D, Li X, et al. Synergistic combination therapy of lung cancer: Cetuximab functionalized nanostructured lipid carriers for the co-delivery of paclitaxel and 5-Demethylnobiletin. Biomed Pharmacother. 2019;118:109225. doi: 10.1016/j.biopha.2019.109225. PubMed DOI

Draghi A, Chamberlain CA, Furness A, Donia M. Acquired resistance to cancer immunotherapy. Semin Immunopathol. 2019;41:31–40. doi: 10.1007/s00281-018-0692-y. PubMed DOI

Gou Q, Dong C, Xu H, Khan B, Jin J, Liu Q, et al. PD-L1 degradation pathway and immunotherapy for cancer. Cell Death & Disease. Nature Publishing Group; 2020;11:1–7, 10.1038/s41419-020-03140-2. PubMed PMC

Nowicki TS, Hu-Lieskovan S, Ribas A. Mechanisms of Resistance to PD-1 and PD-L1 blockade. Cancer J. 2018;24:47–53. doi: 10.1097/PPO.0000000000000303. PubMed DOI PMC

Furukawa K, Nagano T, Tachihara M, Yamamoto M, Nishimura Y. Interaction between Immunotherapy and Antiangiogenic Therapy for Cancer. Molecules 2020;25, 10.3390/molecules25173900. PubMed PMC

Yin S-Y, Yang N-S, Lin T-J. Phytochemicals Approach for Developing Cancer Immunotherapeutics. Front Pharmacol 2017;8, 10.3389/fphar.2017.00386. PubMed PMC

Kopustinskiene DM, Jakstas V, Savickas A, Bernatoniene J. Flavonoids as Anticancer Agents. Nutrients 2020;12, 10.3390/nu12020457. PubMed PMC

Kumar AR, Devan AR, Nair B, Nath LR. Anti-VEGF Mediated Immunomodulatory Role of Phytochemicals: Scientific Exposition for Plausible HCC Treatment. Curr Drug Targets. 2021 doi: 10.2174/1389450122666210203194036. PubMed DOI

Awan FT, Jones JA, Maddocks K, Poi M, Grever MR, Johnson A, et al. A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy. Ann Hematol. 2016;95:1137–1143. doi: 10.1007/s00277-016-2683-1. PubMed DOI PMC

Fan Y, Li S, Ding X, Yue J, Jiang J, Zhao H, et al. First-in-class immune-modulating small molecule Icaritin in advanced hepatocellular carcinoma: preliminary results of safety, durable survival and immune biomarkers. BMC Cancer. 2019;19:279. doi: 10.1186/s12885-019-5471-1. PubMed DOI PMC

Xu L, Zhang Y, Tian K, Chen X, Zhang R, Mu X, et al. Apigenin suppresses PD-L1 expression in melanoma and host dendritic cells to elicit synergistic therapeutic effects. J Exp Clin Cancer Res 2018;37, 10.1186/s13046-018-0929-6. PubMed PMC

Cimini A, d’Angelo M, Benedetti E, D’Angelo B, Laurenti G, Antonosante A, et al. Flavopiridol: An Old Drug With New Perspectives? Implication for Development of New Drugs. J Cell Physiol. 2017;232:312–322. doi: 10.1002/jcp.25421. PubMed DOI

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