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Molecular mechanisms of action of quercetin in cancer: recent advances

  • Review
  • Published:
Tumor Biology

Abstract

In the last few decades, the scientific community has discovered an immense potential of natural compounds in the treatment of dreadful diseases such as cancer. Besides the availability of a variety of natural bioactive molecules, efficacious cancer therapy still needs to be developed. So, to design an efficacious cancer treatment strategy, it is essential to understand the interactions of natural molecules with their respective cellular targets. Quercetin (Quer) is a naturally occurring flavonol present in many commonly consumed food items. It governs numerous intracellular targets, including the proteins involved in apoptosis, cell cycle, detoxification, antioxidant replication, and angiogenesis. The weight of available synergistic studies vigorously fortifies the utilization of Quer as a chemoprevention drug. This extensive review covers various therapeutic interactions of Quer with their recognized cellular targets involved in cancer treatment.

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References

  1. Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer. 2003;3:768–80.

    Article  CAS  PubMed  Google Scholar 

  2. Smith JJ. The world of science. Am J Sci. 1999;36:234–5.

    Google Scholar 

  3. Tuli HS, Kumar G, Kashyap D, Sharma AK, Sandhu SS. Apoptotic effect of cordycepin on A549 human lung cancer cell line. Turk J Biol. 2015;39:306–11.

    Article  CAS  Google Scholar 

  4. Tuli HS, Chaudhary P, Beniwal V, Sharma AK. Microbial pigments as natural color sources: current trends and future perspectives. J Food Sci Technol. 2014;52:4669–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects and safety. Annu Rev Nutr. 2002;22:19–34.

    Article  CAS  PubMed  Google Scholar 

  6. Kandaswami C, Lee LT, Lee PP, Hwang JJ, Ke FC, Huang YT, Lee MT. The antitumor activities of flavonoids. In Vivo. 2005;19:895–909.

    PubMed  Google Scholar 

  7. Erlund I. Review of flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology. Nutr Res. 2004;24:851–74.

    Article  CAS  Google Scholar 

  8. Chien SY, Wu YC, Chung JG. Quercetin-induced apoptosis acts through mitochondrial and caspase-3-dependent pathways in human breast cancer MDA-MB-231 cells. Hum Exp Toxicol. 2009;28:493–503.

    Article  CAS  PubMed  Google Scholar 

  9. Kumar S, Pandey A. Chemistry and biological activities of flavonoids: an overview. Sci World J. 2013;2013:1–16.

    Google Scholar 

  10. Ong C, Tran E, Nguyen T, Ong C, Lee S, Lee J, Ng C, Leong C, Huynh H. Quercetin-induced growth inhibition and cell death in nasopharyngeal carcinoma cells are associated with increase in bad and hypophosphorylated retinoblastoma expressions. Oncol Rep. 2004;11:727–33.

    CAS  PubMed  Google Scholar 

  11. Lautraite S, Musonda AC, Doehmer J, Edwards GO, Chipman JK. Flavonoids inhibit genetic toxicity produced by carcinogens in cells expressing CYP1A2 and CYP1A1. Mutagenesis. 2002;17:45–53.

    Article  CAS  PubMed  Google Scholar 

  12. Vijayababu MR, Arunkumar A, Kanagaraj P, Venkataraman P, Krishnamoorthy G, Arunakaran J. Quercetin downregulates matrix metalloproteinases 2 and 9 proteins expression in prostate cancer cells (PC-3). Mol Cell Biochem. 2006;287:109–16.

    Article  CAS  PubMed  Google Scholar 

  13. Tan WF, Lin LP, Li MH, Zhang YX, Tong YG, Xiao D, Ding J. Quercetin, a dietary-derived flavonoid, possesses antiangiogenic potential. Eur J Pharmacol. 2003;459:255–62.

    Article  CAS  PubMed  Google Scholar 

  14. Chen X. Protective effects of quercetin on liver injury induced by ethanol. Pharmacogn Mag. 2010;6:135–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tuli HS, Sandhu SS, Sharma AK. Pharmacological and therapeutic potential of cordyceps with special reference to cordycepin. 3. Biotech. 2013;4:1–12.

    Google Scholar 

  16. Kashyap D, Tuli HS, Sharma AK. Ursolic acid (UA): a metabolite with promising therapeutic potential. Life Sci. 2016;146:201–13.

    Article  CAS  PubMed  Google Scholar 

  17. Russo M, Palumbo R, Tedesco I, Mazzarella G, Russo P, Iacomino G, Russo GL. Quercetin and anti-CD95 (Fas/Apo1) enhance apoptosis in HPB-ALL cell line. FEBS Lett. 1999;462:322–8.

    Article  CAS  PubMed  Google Scholar 

  18. Wang IK, Lin-Shiau SY, Lin JK. Induction of apoptosis by apigenin and related flavonoids through cytochrome c release and activation of caspase-9 and caspase-3 in leukaemia HL-60 cells. Eur J Cancer. 1999;35:1517–25.

    Article  CAS  PubMed  Google Scholar 

  19. Aalinkeel R, Bindukumar B, Reynolds JL, Sykes DE, Mahajan SD, Chada KC, Schwartz SA. The dietary bioflavonoid, quercetin, selectively induces apoptosis of prostate cancer cells by down-regulating the expression of heat shock protein 90. Prostate. 2008;68:1773–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kim G, Jang H. Protective mechanism of quercetin and rutin using glutathione metabolism on H2O2-induced oxidative stress in HepG2 cells. Ann N Y Acad Sci. 2009;1171:530–7.

    Article  CAS  PubMed  Google Scholar 

  21. Haghiac M, Walle T. Quercetin induces necrosis and apoptosis in SCC-9 oral cancer cells. Nutr Cancer. 2005;53:220–31.

    Article  CAS  PubMed  Google Scholar 

  22. Chou CC, Yang JS, Lu HF, Wan S, Lo C, Wu CC, Lin JP, Tang NY, Chung JG, Chou MJ, Teng YH, Chen DR. Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells. Arch Pharm Res. 2010;8:1181–91.

    Article  CAS  Google Scholar 

  23. Mozhgan FS, Seyed BJ, Bahareh H. The Cuscuta kotschyana effects on breast cancer cells line MCF7. J Med Plants Res. 2011;5:6344–51.

    Google Scholar 

  24. Niu G, Yin S, Xie S, Li Y, Nie D, Ma L, Wang X, Wu Y. Quercetin induces apoptosis by activating caspase-3 and regulating Bcl-2 and cyclooxygenase-2 pathways in human HL-60 cells. Acta Biochim Biophys Sin. 2011;43:30–7.

    Article  CAS  PubMed  Google Scholar 

  25. Russo M, Spagnuolo C, Bilotto S, Tedesco I, Maiani G, Russo GL. Inhibition of protein kinase CK2 by quercetin enhances CD95-mediated apoptosis in a human thymus-derived T cell line. Food Res Int. 2014;63:244–51.

    Article  CAS  Google Scholar 

  26. Shen SC, Lee WR, Yang LY, Tsai HH, Yang LL, Chen YC. Quercetin enhancement of arsenic-induced apoptosis via stimulating ROS-dependent p53 protein ubiquitination in human HaCaT keratinocytes. Exp Dermatol. 2012;21:370–5.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang JY, Yi T, Liu J, Zhao ZZ, Chen HB. Quercetin induces apoptosis via the mitochondrial pathway in KB and KBv200 cells. J Agric Food Chem. 2013;61:2188–95.

    Article  CAS  PubMed  Google Scholar 

  28. Hu J, Yu Q, Zhao F, Ji J, Jiang Z, Chen X, Gao P, Ren Y, Shao S, Zhang L, Yan M. Protection of quercetin against triptolide-induced apoptosis by suppressing oxidative stress in rat Leydig cells. Chem Biol Interact. 2015;240:38–46.

    Article  CAS  PubMed  Google Scholar 

  29. Banerjee T, Van der Vliet A, Ziboh VA. Down regulation of COX-2 and iNOS by amentoflavone and quercetin in A549 human lung adenocarcinoma cell line. Prostaglandins Leukot Essent Fat Acids. 2002;66:485–92.

    Article  CAS  Google Scholar 

  30. Mutoh M, Takahashi M, Fukuda K, Komatsu H, Enya T, Matsushima-Hibiya Y, Mutoh H. Suppression by flavonoids of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells: structure–activity relationship. Jpn J Cancer Res. 2000;91:686–91.

    Article  CAS  PubMed  Google Scholar 

  31. Cheong E, Ivory K, Doleman J, Parker ML, Rhodes M, Johnson IT. Synthetic and naturally occurring COX-2 inhibitors suppress proliferation in a human oesophageal adenocarcinoma cell line (OE33) by inducing apoptosis and cell cycle arrest. Carcinogenesis. 2004;25:1945–52.

    Article  CAS  PubMed  Google Scholar 

  32. Chen D, Daniel KG, Chen MS, Kuhn DJ, Landis-Piwowar KR, Dou QP. Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. Biochem Pharmacol. 2005;69:1421–32.

    Article  CAS  PubMed  Google Scholar 

  33. Vijayababu MR, Kanagaraj P, Arunkumar A, Ilangovan R, Aruldhas MM, Arunakaran J. Quercetin-induced growth inhibition and cell death in prostatic carcinoma cells (PC-3) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression. J Cancer Res Clin Oncol. 2005;13:765–71.

    Article  CAS  Google Scholar 

  34. Volate SR, Davenport DM, Muga SJ, Wargovich MJ. Modulation of aberrant crypt foci and apoptosis by dietary herbal supplements (quercetin, curcumin, silymarin, ginseng and rutin). Carcinogenesis. 2005;26:1450–6.

    Article  CAS  PubMed  Google Scholar 

  35. Kim H, Moon JY, Ahn KS, Cho SK. Quercetin induces mitochondrial mediated apoptosis and protective autophagy in human glioblastoma U373MG cells. Oxidative Med Cell Longev. 2013;2013:1–10.

    Google Scholar 

  36. Han Y, Yu H, Wang J, Ren Y, Su X, Shi Y. Quercetin alleviates myocyte toxic and sensitizes anti-leukemic effect of Adriamycin. Hematology. 2015;20:276–83.

    Article  CAS  PubMed  Google Scholar 

  37. Granado-Serrano AB, Martin MA, Bravo L, Ramos S. Quercetin induces apoptosis via caspase activation, regulation of Bcl −2, and inhibition of PI-3-kinase/Akt and ERK pathway in a human hepatoma cell line (HepG2). J Nutr. 2006;136:2715–21.

    CAS  PubMed  Google Scholar 

  38. Choi J, Kim J, Lee J, Kang C, Kwon H, Yoo Y, Kim T, Lee Y, Lee S. Induction of cell cycle arrest and apoptosis in human breast cancer cells by quercetin. Int J Oncol. 2001;19:837–44.

    CAS  PubMed  Google Scholar 

  39. Zhang Q, Zhao XH, Wang ZJ. Cytotoxicity of flavones and flavonols to a human esophageal squamous cell carcinoma cell line KYSE-510 by induction of G2/M arrest and apoptosis. Toxicol in Vitro. 2009;23:797–807.

    Article  CAS  PubMed  Google Scholar 

  40. Lee YK, Hwang JT, Kwon DY, Surh YJ, Park OJ. Induction of apoptosis by quercetin is mediated through AMPKalpha1/ASK1/p38 pathway. Cancer Lett. 2010;292:228–36.

    Article  CAS  PubMed  Google Scholar 

  41. Vidya Priyadarsini R, Senthil Murugan R, Maitreyi S, Ramalingam K, Karunagaran D, Nagini S. The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-kB inhibition. Eur J Pharmacol. 2010;649:84–91.

    Article  CAS  PubMed  Google Scholar 

  42. Chan ST, Yang NC, Huang CS, Liao JW, Yeh SL. Quercetin enhances the antitumor activity of trichostatin A through upregulation of p53 protein expression in vitro and in vivo. PLoS One. 2013;8;doi:10.1371/journal.pone.0054255.

  43. Lee KH, Yoo CG. Simultaneous inactivation of GSK-3β suppresses quercetin-induced apoptosis by inhibiting the JNK pathway. Am J Phys Lung Cell Mol Phys. 2013;304:782–9.

    Google Scholar 

  44. Altundal EM, Kasac T, YJlmaz AM, Karademir B, Koçtürk S, Taga Y, Yalçin AS. Quercetin-induced cell death in human papillary thyroid cancer (B-CPAP). Cells J Thyroid Res. 2015;2016:1–10.

    Article  Google Scholar 

  45. Kim MC, Lee HJ, Lim B, Ha KT, Kim SY, So I, Kim BJ. Quercetin induces apoptosis by inhibiting MAPKs and TRPM7 channels in AGS cells. Int J Mol Med. 2014;33:1657–63.

    CAS  PubMed  Google Scholar 

  46. Zhao P, Mao JM, Zhang SY, Zhou ZQ, Tan Y, Zhang Y. Quercetin induces HepG2 cell apoptosis by inhibiting fatty acid biosynthesis. Oncol Lett. 2014;8:765–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Refolo MG, D’Alessandro R, Malerba N, Laezza C, Bifulco M, Messa C, Caruso MG, Notarnicola M, Tutino V. Anti-proliferative and pro apoptotic effects of flavonoid quercetin are mediated by CB1 receptor in human colon cancer cell lines. J Cell Physiol. 2015;230:2973–80.

    Article  CAS  PubMed  Google Scholar 

  48. Gulati N, Laudet B, Zohrabian MV, Murali R, Jhanwar-Uniyal M. The antiproliferative effect of quercetin in cancer cells is mediated via inhibition of the PI3K-Akt/PKB pathway. Anticancer Res. 2006;26:1177–82.

    CAS  PubMed  Google Scholar 

  49. Kim GT, Lee SH, Kim JI, Kim YM. Quercetin regulates the sestrin 2-AMPK-p38 MAPK signaling pathway and induces apoptosis by increasing the generation of intracellular ROS in a p53-independent manner. Int J Mol Med. 2014;33:863–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Cosan DT, Soyocak A, Basaran A, Değirmenci I, Güneş HV, Bal C. How does quercetin and tamoxifen affect the apoptosis of colon cancer cells? Osmangazi Tip Dergisi. 2015;37:14–20.

    Google Scholar 

  51. Lee WJ, Hsiao M, Chang JL, Yang SF, Tseng TH, Cheng CW, Chow JM, Lin KH, Lin YW, Liu CC, Lee LM, Chien MH. Quercetin induces mitochondrial-derived apoptosis via reactive oxygen species-mediated ERK activation in HL-60 leukemia cells and xenograft. Arch Toxicol. 2015;89:1103–17.

    Article  CAS  PubMed  Google Scholar 

  52. Mukherjee A, Khuda-Bukhsh AR. Quercetin down-regulates IL-6/STAT-3 signals to induce mitochondrial-mediated apoptosis in a non-small-cell lung-cancer cell line, A549. Aust J Pharm. 2015;18:19–26.

    Google Scholar 

  53. Ranganathan S, Halagowder D, Sivasithambaram ND. Quercetin suppresses twist to induce apoptosis in MCF-7 breast cancer cells. PLoS One. 2015;10:e0141370. doi:10.1371/journal.pone.0141370.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Lou G, Liu Y, Wu S, Xue J, Yang F, Fu H, Zheng M, Chen Z. The p53/miR-34a/SIRT1 positive feedback loop in quercetin-induced apoptosis. Cell Physiol Biochem. 2015;35:2192–202.

    Article  CAS  PubMed  Google Scholar 

  55. Chen X, Dong XS, Gao HY, Jiang YF, Jin YL, Chang YY, Chen LY, Wang JH. Suppression of HSP27 increases the anti-tumor effects of quercetin in human leukemia U937 cells. Mol Med Rep. 2016;13:689–96.

    CAS  PubMed  Google Scholar 

  56. Kumar G, Tuli HS, Mittal S, Shandilya JK, Tiwari A, Sandhu SS. Isothiocyanates: a class of bioactive metabolites with chemopreventive potential. Tumor Biol. 2015;36:4005–16.

    Article  CAS  Google Scholar 

  57. Kumar G, Mittal S, Sak K, Tuli HS. Molecular mechanisms underlying chemopreventive potential of curcumin: current challenges and future perspectives. Life Sci. 2016;148:313–28.

    Article  CAS  PubMed  Google Scholar 

  58. Moon SK, Cho GO, Jung SY, Gal SW, Kwon TK, Lee YC, Madamanchi NR, Kim CH. Quercetin exerts multiple inhibitory effects on vascular smooth muscle cells: role of ERK1/2, cell-cycle regulation, and matrix metalloproteinase-9. Biochem Biophys Res Commun. 2003;301:1069–78.

    Article  CAS  PubMed  Google Scholar 

  59. Kuo PC, Liu HF, Chao JI. Survivin and p53 modulate quercetin-induced cell growth inhibition and apoptosis in human lung carcinoma cells. J Biol Chem. 2004;279:55875–85.

    Article  CAS  PubMed  Google Scholar 

  60. Mu C, Jia P, Yan Z, Lin X, Li X, Lin H. Quercetin induces cell-cycle G1 arrest through elevating Cdk inhibitors p21 and p27 in human hepatoma cell line (HepG2). Methods Find Exp Clin Pharmacol. 2007;29:179–83.

    Article  CAS  PubMed  Google Scholar 

  61. Jeong JH, An JY, Kwon YT, Rhee JG, Lee YJ. Effects of low dose quercetin: cancer cell-specific inhibition of cell cycle progression. J Cell Biochem. 2009;106:73–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Duo J, Ying GG, Wang GW, Zhang L. Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation. Mol Med Rep. 2012;5:1453–6.

    CAS  PubMed  Google Scholar 

  63. Atashpour S, Fouladdel S, Movahhed TK. Quercetin induces cell cycle arrest and apoptosis in CD133+ cancer stem cells of human colorectal HT29 cancer cell line and enhances anticancer effects of doxorubicin. Iran J Basic Med Sci. 2015;18:635–43.

    PubMed  PubMed Central  Google Scholar 

  64. Casella ML, Parody JP, Ceballos MP, Quiroga AD, Ronco MT, Francés DE, Monti JA, Pisani GB, Carnovale CE, Carrillo MC, de Luján Alvarez M. Quercetin prevents liver carcinogenesis by inducing cell cycle arrest, decreasing cell proliferation and enhancing apoptosis. Mol Nutr Food Res. 2014;58:289–300.

    Article  CAS  PubMed  Google Scholar 

  65. Ren MX, Deng XH, Ai F, Yuan GY, Song HY. Effect of quercetin on the proliferation of the human ovarian cancer cell line SKOV-3 in vitro. Exp Ther Med. 2015;10:579–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Lee YJ, Lee DM, Lee SH. Nrf2 expression and apoptosis in quercetin-treated malignant mesothelioma cells. Mol Cell. 2015;38:416–25.

    Article  CAS  Google Scholar 

  67. Nebert DW, Dalton TP. The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer. 2006;6:947–60.

    Article  CAS  PubMed  Google Scholar 

  68. Obach RS. Inhibition of human cytochrome P450 enzymes by constituents of St. John’s wort, an herbal preparation used in the treatment of depression. J Pharmacol Exp Ther. 2000;294:88–95.

    CAS  PubMed  Google Scholar 

  69. Schwarz D, Kisselev P, Roots I. St. John’s wort extracts and some of their constituents potently inhibit ultimate carcinogen formation from benzo [a] pyrene-7, 8-dihydrodiol by human CYP1A1. Cancer Res. 2003;63:8062–8.

    CAS  PubMed  Google Scholar 

  70. Choi JS, Li X. Enhanced diltiazem bioavailability after oral administration of diltiazem with quercetin to rabbits. Int J Pharm. 2005;297:1–8.

    Article  CAS  PubMed  Google Scholar 

  71. Shin SC, Choi JS, Li X. Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. Int J Pharm. 2006;313:144–9.

    Article  CAS  PubMed  Google Scholar 

  72. Yeh SL, Wu SH. Effects of quercetin of β-apo-8′-carotenal-induced DNA damage and cytochrome P1A2 expression in A549 cells. Chem Biol Interact. 2006;163:199–206.

    Article  CAS  PubMed  Google Scholar 

  73. Schwarz D, Kisselev P, Roots I. CYP1A1 genotype-selective inhibition of benzo [a] pyrene activation by quercetin. Eur J Cancer. 2005;41:151–8.

    Article  CAS  PubMed  Google Scholar 

  74. Haza AI, Coto AL, Morales P. Comparison of the ability of myricetin and quercetin to modulate the oxidative DNA damage induced by heterocyclic amines. Food Nutr Sci. 2011;2:356–65.

    Article  CAS  Google Scholar 

  75. Kang IH, Kim HJ, Oh H, Park YI, Dong MS. Biphasic effects of the flavonoids quercetin and naringenin on the metabolic activation of 2-amino-3,5-dimethylimidazo [4,5-f] quinoline by salmonella typhimurium TA1538 co-expressing human cytochrome P450 1 A2, NADPH-cytochrome P450 reductase, and cytochrome b5. Mutat Res. 2004;545:37–47.

    Article  CAS  PubMed  Google Scholar 

  76. Hsiu SL, Hou YC, Wang YH, Tsao CW, Su SF, Chao PD. Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats. Life Sci. 2002;72:227–35.

    Article  CAS  PubMed  Google Scholar 

  77. Zendulka O, Zahradníková L, Juřica J, Totušek J. The influence of trans-resveratrol and quercetin on the activity of CYP1A2 in rat. Czech J Food Sci. 2008;26:S60–4.

    CAS  Google Scholar 

  78. Chen Y, Xiao P, Ou-Yang DS, Fan L, Guo D, Wang YN, Han Y, Tu JH, Zhou G, Huang YF, Zhou HH. Simultaneous action of the flavonoid quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, n-acetyltransferase and xanthine oxidase activity in healthy volunteers. Clin Exp Pharmacol Physiol. 2009;36:828–33.

    Article  CAS  PubMed  Google Scholar 

  79. Li X, Choi JS. Effects of quercetin on the pharmacokinetics of etoposide after oral or intravenous administration of etoposide in rats. Anticancer Res. 2009;29:1411–6.

    CAS  PubMed  Google Scholar 

  80. Choi JS, Piao YJ, Kang KW. Effects of quercetin on the bioavailability of doxorubicin in rats: role of CYP3A4 and P-gp inhibition by quercetin. Arch Pharm Res. 2011;34:607–13.

    Article  CAS  PubMed  Google Scholar 

  81. Kwak MK, Itoh K, Yamamoto M, Sutter TR, Kensler TW. Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione. Mol Med. 2001;7:135–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Tan XL, Spivack SD. Dietary chemoprevention strategies for induction of phase II xenobiotic-metabolizing enzymes in lung carcinogenesis: a review. Lung Cancer. 2009;65:129–37.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Kansanen E, Jyrkkänen HK, Volger OL, Leinonen H, Kivelä AM, Häkkinen SK, Woodcock SR, Schopfer FJ, Horrevoets AJ, Ylä-Herttuala S, Freeman BA. Nrf2-dependent and -independent responses to nitro-fatty acids in human endothelial cells: identification of heat shock response as the major pathway activated by nitro-oleic acid. J Biol Chem. 2009;284:33233–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells. 2011;16:123–40.

    Article  CAS  PubMed  Google Scholar 

  85. Kansanen E, Jyrkkänen HK, Levonen AL. Activation of stress signaling pathways by electrophilic oxidized and nitrated lipids. Free Radic Biol Med. 2012;52:973–82.

    Article  CAS  PubMed  Google Scholar 

  86. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci. 2002;99:11908–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tanigawa S, Fujii M, Hou X. Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med. 2007;42:1690–703.

    Article  CAS  PubMed  Google Scholar 

  88. Odenthal J, Van Heumen BW, Roelofs HM, te Morsche RH, Marian B, Nagengast FM, Peters WH. The influence of curcumin, quercetin, and eicosapentaenoic acid on the expression of phase II, detoxification enzymes in the intestinal cell lines HT-29, Caco-2, HuTu 80, and LT97. Nutr Cancer. 2012;64:856–63.

    Article  CAS  PubMed  Google Scholar 

  89. Ramyaa P, Krishnaswamy K, Padma VV. Quercetin modulates OTA-induced oxidative stress and redox signaling in HepG2 cells—up regulation of Nrf2 expression and down regulation of NF-kβ and COX-2. Biochim Biophys Acta. 1840;2014:681–92.

    Google Scholar 

  90. Shi Y, Liang XC, Zhang H, Wu QL, Qu L, Sun Q. Quercetin protects rat dorsal root ganglion neurons against high glucose-induced injury in vitro through Nrf-2/HO-1 activation and NF-kβ inhibition. Acta Pharmacol Sin. 2013;34:1140–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lee YJ, Song JH, Oh MH, Lee YJ, Kim YB, Im JH, Lee SH. ERK1/2 activation in quercetin-treated BEAS-2B cell plays a role in Nrf2-driven HO-1 expression. Mol Cell Toxicol. 2011;7:347–55.

    Article  CAS  Google Scholar 

  92. Chow JM, Shen SC, Huan SK, Lin HY, Chen YC. Quercetin, but not rutin and quercitrin, prevention of H2O2-induced apoptosis via anti-oxidant activity and heme oxygenase 1 gene expression in macrophages. Biochem Pharmacol. 2005;69:1839–51.

    Article  CAS  PubMed  Google Scholar 

  93. Yao P, Nussler A, Liu L, Hao L, Song F, Schirmeier A, Nussler A. Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways. J Hepatol. 2007;47:253–61.

    Article  CAS  PubMed  Google Scholar 

  94. Lee KW, Kang NJ, Heo YS, Rogozin EA, Pugliese A, Hwang MK, Bowden GT, Bode AM, Lee HJ, Dong Z. Raf and MEK protein kinases are direct molecular targets for the chemopreventive effect of quercetin, a major flavonol in red wine. Cancer Res. 2008;68:946–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Granado-Serrano AB, Martín MA, Bravo L, Goya L, Ramos L. Quercetin modulates Nrf2 and glutathione-related defenses in HepG2 cells: involvement of p38. Chem Biol Interact. 2012;195:154–64.

    Article  CAS  PubMed  Google Scholar 

  96. Schadich E, Hlaváč J, Volná T, Varanasi L, Hajdúch M, Džubák P. Effects of ginger phenylpropanoids and quercetin on Nrf2-ARE pathway in human BJ fibroblasts and HaCaT keratinocytes. BioMed Res Int. 2016;2015:1–6.

    Article  Google Scholar 

  97. Sun GY, Chen Z, Jasmer KJ, Chuang DY, Gu Z, Hannink M, Simonyi A. Quercetin attenuates inflammatory responses in BV-2 microglial cells: role of MAPKs on the Nrf2 pathway and induction of Heme oxygenase-1. PLoS One. 2015; 10(10); doi:10.1371/journal.pone.0141509.

  98. Xu XR, Yu HT, Yang Y, Hang L, Yang XW, Ding SH. Quercetin phospholipid complex significantly protects against oxidative injury in ARPE-19 cells associated with activation of Nrf2 pathway. Eur J Pharmacol. 2016;770:1–8.

    Article  CAS  PubMed  Google Scholar 

  99. Liu CM, Ma JQ, Xie WR, Liu SS, Feng ZJ, Zheng GH, Wang AM. Quercetin protects mouse liver against nickel-induced DNA methylation and inflammation associated with the Nrf2/HO-1 and p38/STAT1/NF-kβ pathway. Food Chem Toxicol. 2015;82:19–26.

    Article  CAS  PubMed  Google Scholar 

  100. Ji LL, Sheng YC, Zheng ZY, Shi L, Wang ZT. 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.

    Article  CAS  PubMed  Google Scholar 

  101. Tuli HS, Sandhu SS, Sharma AK, Gandhi P. Anti-angiogenic activity of the extracted fermentation broth of an entomopathogenic fungus, Cordyceps militaris 3936. Int J Pharm Pharm Sci. 2014;6(7):581–3.

    Google Scholar 

  102. Tuli HS, Kashyap D, Bedi SK, Kumar P, Kumar G, Sandhu SS. Molecular aspects of metal oxide nanoparticle (MO-NPs) mediated pharmacological effects. Life Sci. 2015;143:71–9.

    Article  CAS  PubMed  Google Scholar 

  103. Battegay EJ. Angiogensis: mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med. 1995;73:333–46.

    Article  CAS  PubMed  Google Scholar 

  104. Klagsbrun M, Moses MA. Molecular angiogenesis. Chem Biol. 1999;6:217–24.

    Article  Google Scholar 

  105. Hayashi A, Gillen AC, Lott JR. Effects of daily oral administration of quercetin chalcone and modified citrus pectin on implanted colon-25 tumor growth in Balb-c mice. Altern Med Rev. 2000;5:546–52.

    CAS  PubMed  Google Scholar 

  106. Igura K, Ohta T, Kuroda Y, Kaji K. Resveratrol and quercetin inhibit angiogenesis in vitro. Cancer Lett. 2001;171:11–6.

    Article  CAS  PubMed  Google Scholar 

  107. Argyriou AA, Giannopoulou E, Kalofonos HP. Angiogenesis and anti-angiogenic molecularly targeted therapies in malignant gliomas. Oncology. 2009;77:1–11.

    Article  CAS  PubMed  Google Scholar 

  108. Kong L, Wu K, Lin H. Inhibitory effects of quercetin on angiogenesis of experimental mammary carcinoma. Chin J Clin Oncol. 2005;2:631–6.

    Article  CAS  Google Scholar 

  109. Jackson SJ, Venema RC. Quercetin inhibits eNOS, microtubule polymerization, and mitotic progression in bovine aortic endothelial cells. J Nutr. 2006;136:1178–84.

    CAS  PubMed  Google Scholar 

  110. Sagar SM, Yance D, Wong RK. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer—part 1. Curr Oncol. 2006;13:14–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Mojzis J, Varinska L, Mojzisova G, Kostova I, Mirossay L. Antiangiogenic effects of flavonoids and chalcones. Pharmacol Res. 2008;57:259–65.

    Article  CAS  PubMed  Google Scholar 

  112. Miao Z, Feng J, Ding J. Newly discovered angiogenesis inhibitors and their mechanisms of action. Acta Pharmacol Sin. 2012;33:1103–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Pratheeshkumar P, Budhraja A, Son YO, Wang X, Zhang Z, Ding S, Wang L, Hitron A, Lee JC, Xu M, Chen G, Luo J, Shi X. Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR-2 regulated AKT/mTOR/P70S6K signaling pathways. PLoS One. 2012; 7(10); doi: 10.1371/journal.pone.0047516.

  114. Li F, Bai Y, Zhao M, Huang L, Li S, Li X, Chen Y. Quercetin inhibits vascular endothelial growth factor-induced choroidal and retinal angiogenesis in vitro. Ophthalmic Res. 2015;53:109–16.

    Article  CAS  PubMed  Google Scholar 

  115. Zhao D, Qin C, Fan X, Li Y, Gu B. Inhibitory effects of quercetin on angiogenesis in larval zebrafish and human umbilical vein endothelial cells. Eur J Pharmacol. 2014;723:360–7.

    Article  CAS  PubMed  Google Scholar 

  116. Famil Samavati S, Mohammadi-Motlagh HR, Mostafaie A. A highly pure sub-fraction of shallot extract with potent in vitro anti-angiogenic activity. Int J Mol Cell Med. 2014;3:237–45.

    PubMed  PubMed Central  Google Scholar 

  117. Maniago KGN, Mari CGS, Pareja MC. Angiogenic effect of Curcuma longa Linn. (turmeric) tea powder on the chorioallantoic membrane of 10-day old Anas luzonica (duck) eggs. Ann Biol Res. 2014;5:32–7.

    Google Scholar 

  118. Cao HH, Tse AK, Kwan HY, Yu H, Cheng CY, Su T, Fong WF, Yu ZL. Quercetin exerts anti-melanoma activities and inhibits STAT3 signaling. Biochem Pharmacol. 2014;87:424–34.

    Article  CAS  PubMed  Google Scholar 

  119. Lin CW, Hou WC, Shen SC, Juan SH, Ko CH, Wang LM, Chen YC. Quercetin inhibition of tumor invasion via suppressing PKCd/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis. 2008;29:1807–15.

    Article  CAS  PubMed  Google Scholar 

  120. Lai WW, Hsu SC, Chueh FS, Chen YY, Yang JS, Lin JP, Lien JC, Tsai CH, Chung JG. Quercetin inhibits migration and invasion of SAS human oral cancer cells through inhibition of NF-kβ and matrix metalloproteinase-2/-9 signaling pathways. Anticancer Res. 2013;33:1941–50.

    CAS  PubMed  Google Scholar 

  121. Conklin CMJ, Bechberger JF, MacFabe D, Guthrie N, Kurowska EM, Naus CC. Genistein and quercetin increase connexin43 and suppress growth of breast cancer cells. Carcinogenesis. 2007;28:93–100.

    Article  CAS  PubMed  Google Scholar 

  122. Yang F, Jiang X, Song L, Wang H, Mei Z, Xu Z, Xing N. Quercetin inhibits angiogenesis through thrombospondin-1 upregulation to antagonize human prostate cancer PC-3 cell growth in vitro and in vivo. Oncol Rep. 2016;35:1602–10.

    CAS  PubMed  Google Scholar 

  123. Chen Y, Li F, Meng X, Li X. Suppression of retinal angiogenesis by quercetin in a rodent model of retinopathy of prematurity. Zhonghua Yi Xue Za Zhi. 2015;95:1113–5.

    CAS  PubMed  Google Scholar 

  124. Cao HH, Cheng CY, Su T, Fu XQ, Guo H, Li T, Tse AKW, Kwan HY, Yu H, Yu ZL. Quercetin inhibits HGF/c-met signaling and HGFstimulated melanoma cell migration and invasion. Mol Cancer. 2015;14:103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Brito AF, Ribeiro M, Abrantes AM, Pires AS, Teixo RJ, Tralhão JG, Botelho MF. Quercetin in cancer treatment, alone or in combination with conventional therapeutics? Curr Med Chem. 2015;22:3025–39.

    Article  CAS  PubMed  Google Scholar 

  126. Kuhar M, Imran S, Singh N. Curcumin and quercetin combined with cisplatin to induce apoptosis in human laryngeal carcinoma Hep-2 cells through the mitochondrial pathway. J Cancer Mol. 2007;3:121–8.

    CAS  Google Scholar 

  127. Senggunprai L, Kukongviriyapan V, Prawan A, Kukongviriyapan U. Quercetin and EGCG exhibit chemopreventive effects in cholangiocarcinoma cells via suppression of JAK/STAT signaling pathway. Phytother Res. 2014;28:841–8.

    Article  CAS  PubMed  Google Scholar 

  128. Appari M, Babu KR, Kaczorowski A, Gross W, Herr I. Sulforaphane, quercetin and catechins complement each other in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibition. Int J Oncol. 2014;45:1391–400.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Wang G, Song L, Wang H, Xing N. Quercetin synergizes with 2-methoxyestradiol inhibiting cell growth and inducing apoptosis in human prostate cancer cells. Oncol Rep. 2013;30:357–63.

    CAS  PubMed  Google Scholar 

  130. Nessa MU, Beale P, Chan C, Yu JQ, Huq F. Synergism from combinations of cisplatin and oxaliplatin with quercetin and thymoquinone in human ovarian tumour models. Anticancer Res. 2011;31:3789–97.

    CAS  PubMed  Google Scholar 

  131. Zhang X, Guo Q, Chen J, Chen Z. Quercetin enhances cisplatin sensitivity of human osteosarcoma cells by modulating microRNA-217-KRAS Axis. Mol Cell. 2015;38:638–42.

    Article  CAS  Google Scholar 

  132. Hsieh TC, Wu JM. Targeting CWR22rv1 prostate cancer cell proliferation and gene expression by combinations of the phytochemicals EGCG, genistein and quercetin. Anticancer Res. 2009;29:4025–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Bądziul D, Jakubowicz-Gil J, Langner E, Rzeski W, Głowniak K, Gawron A. The effect of quercetin and imperatorin on programmed cell death induction in T98G cells in vitro. Pharmacol Rep. 2014;66:292–300.

    Article  PubMed  CAS  Google Scholar 

  134. Arias N, Macarulla MT, Aguirre L, Milton I, Portillo MP. The combination of resveratrol and quercetin enhances the individual effects of these molecules on triacylglycerol metabolism in white adipose tissue. Eur J Nutr. 2016;55:341–8.

    Article  CAS  PubMed  Google Scholar 

  135. Atashpour S, Fouladdel S, Movahhed TK, Barzegar E, Hossein M, Ostad SN, Azizi E. Quercetin induces cell cycle arrest and apoptosis in CD133+ cancer stem cells of human colorectal HT29 cancer cell line and enhances anticancer effects of doxorubicin. Iran J Basic Med Sci. 2015;18:635–43.

    PubMed  PubMed Central  Google Scholar 

  136. Di Lorenzo G, Pagliuca M, Perillo T, Zarrella A, Verde A, De Placido S, Buonerba C. Complete response and fatigue improvement with the combined use of cyclophosphamide and quercetin in a patient with metastatic bladder cancer: a case report. Medicine (Baltimore). 2016; 95(5); doi: 10.1097/MD.0000000000002598.

  137. Storniolo A, Raciti M, Cucina A, Bizzarri M, Renzo LD. Quercetin affects Hsp70/IRE1훼 mediated protection from death induced by endoplasmic reticulum stress. Oxidative Med Cell Longev. 2015;2015:1–11.

    Article  Google Scholar 

  138. Yu CP, Wu PP, Hou YC, Lin SP, Tsai SY, Chen CT, Chao PD. Quercetin and rutin reduced the bioavailability of cyclosporine from Neoral, an immunosuppressant, through activating P-glycoprotein and CYP 3A4. J Agric Food Chem. 2011;59:4644–8.

    Article  CAS  PubMed  Google Scholar 

  139. Cermak R, Wein S, Wolffram S, Langguth P. Effects of the flavonol quercetin on the bioavailability of simvastatin in pigs. Eur J Pharm Sci. 2009;38:519–24.

    Article  CAS  PubMed  Google Scholar 

  140. Dupuy J, Larrieu G, Sutra JF, Lespine A, Alvinerie M. Enhancement of moxidectin bioavailability in lamb by a natural flavonoid: quercetin. Vet Parasitol. 2003;112:337–47.

    Article  CAS  PubMed  Google Scholar 

  141. Choi JS, Jo BW, Kim YC. Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin. Eur J Pharm Biopharm. 2004;57:313–8.

    Article  CAS  PubMed  Google Scholar 

  142. Wang YH, Chao PD, Hsiu SL, Wen KC, Hou YC. Lethal quercetin-digoxin interaction in pigs. Life Sci. 2004;74:1191–7.

    Article  CAS  PubMed  Google Scholar 

  143. Choi JS, Han HK. The effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits. J Pharm Pharmacol. 2004;56:1537–42.

    Article  CAS  PubMed  Google Scholar 

  144. Moon YJ, Morris ME. Pharmacokinetics and bioavailability of the bioflavonoid biochanin a: effects of quercetin and EGCG on biochanin a disposition in rats. Mol Pharm. 2007;4:865–72.

    Article  CAS  PubMed  Google Scholar 

  145. Bansal T, Awasthi A, Jaggi M, Khar RK, Talegaonkar S. Pre-clinical evidence for altered absorption and biliary excretion of irinotecan (CPT-11) in combination with quercetin: possible contribution of P-glycoprotein. Life Sci. 2008;83:250–9.

    Article  CAS  PubMed  Google Scholar 

  146. Umathe SN, Dixit PV, Kumar V, Bansod KU, Wanjari MM. Quercetin pretreatment increases the bioavailability of pioglitazone in rats: involvement of CYP3A inhibition. Biochem Pharmacol. 2008;75:1670–6.

    Article  CAS  PubMed  Google Scholar 

  147. Kim KA, Park PW, Park JY. Short-term effect of quercetin on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein, in healthy volunteers. Eur J Clin Pharmacol. 2009;65:609–14.

    Article  CAS  PubMed  Google Scholar 

  148. Zhao LR, Du YJ, Chen L, Liu ZG, Pan YH, Liu JF, Liu B. Quercetin protects against high glucose-induced damage in bone marrow-derived endothelial progenitor cells. Int J Mol Med. 2014;34:1025–31.

    CAS  PubMed  Google Scholar 

  149. Patil SL, Rao NB, Somashekarappa HM, Rajashekhar KP. Antigenotoxic potential of rutin and quercetin in Swiss mice exposed to gamma radiation. Biomed J. 2014;37:305–13.

    Article  PubMed  Google Scholar 

  150. MacGregor JT. Mutagenicity studies of flavonoids in vivo and in vitro. Toxicol Appl Pharmacol. 1979;48:A47.

    Google Scholar 

  151. Sahu RK, Basu R, Sharma A. Genetic toxicological of some plant flavonoids by the micronucleus test. Mutat Res. 1981;89:69–74.

    Article  CAS  PubMed  Google Scholar 

  152. Aravindakshan M, Chauhan PS, Sundaram K. Studies on germinal effects of quercetin, a naturally occurring flavonoid. Mutat Res. 1985;144:99–106.

    Article  CAS  PubMed  Google Scholar 

  153. Caria H, Chaveca T, Laires A, Rueff J. Genotoxicity of quercetin in the micronucleus assay in mouse bone marrow erythrocytes, human lymphocytes, V79 cell line and identification of kinetochore-containing (crest staining) micronuclei in human lymphocytes. Mutat Res. 1995;343:85–94.

    Article  CAS  PubMed  Google Scholar 

  154. Ngomuo AJ, Jones RS. Genotoxicity studies of quercetin and shikimatein vivo in the bone marrow of mice and gastric mucosal cells of rats. Vet Hum Toxicol. 1996;38:176–80.

    CAS  PubMed  Google Scholar 

  155. da Silva J, Herrmann SM, Heuser V, Peres W, Possa Marroni N, Gonzalez-Gallego J, Erdtmann B. Evaluation of the genotoxic effect of rutin and quercetin by comet assay and micronucleus test. Food Chem Toxicol. 2002;40:941–7.

    Article  PubMed  Google Scholar 

  156. Haskins AH, Su C, Engen A, Salinas VA, Maeda J, Uesaka M, Aizawa Y, Kato TA. Data for induction of cytotoxic response by natural and novel quercetin glycosides. Data Brief. 2015;6:262–6.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Stoewsand GS, Anderson JL, Boyd JN, Hrazdina G, Babish JG, Walsh KM, Losco P. Quercetin: a mutagen, not a carcinogen, in Fischer rats. J Toxicol Environ Health. 1984;14:105–14.

    Article  CAS  PubMed  Google Scholar 

  158. Crebelli R, Aquilina G, Falcone E, Carere A. Urinary and faecal mutagenicity in Sprague–Dawley rats dosed with the food mutagens quercetin and rutin. Food Chem Toxicol. 1987;25:9–15.

    Article  CAS  PubMed  Google Scholar 

  159. Pamukcu AM, Yalçiner S, Hatcher JF, Bryan GT. Quercetin, a rat intestinal and bladder carcinogen present in bracken Fern (Pteridium aquilinum). Cancer Res. 1980;40:3468–72.

    CAS  PubMed  Google Scholar 

  160. Dunnick JK, Hailey JR. Toxicity and carcinogenicity studies of quercetin, a natural component of foods. Fundam Appl Toxicol. 1992;19:423–31.

    Article  CAS  PubMed  Google Scholar 

  161. Rangan GK, Wang Y, Harris DCH. Dietary quercetin augments activator protein-1 and does not reduce nuclear factor-kappa B in the renal cortex of rats with established chronic glomerular disease. Nephron. 2000;90:313–9.

    Article  Google Scholar 

  162. Kitamura Y, Nishikawa A, Nakamura H, Furukawa F, Imazawa T, Umemura T, Uchida K, Hirose M. Effects of N-acetylcysteine, quercetin, and phytic acid on spontaneous hepatic and renallesions in LEC rats. Toxicol Pathol. 2005;33:584–92.

    Article  CAS  PubMed  Google Scholar 

  163. Soares VC, Varanda EA, Raddi MS. In vitro basal and metabolism-mediated cytotoxicity of flavonoids. Food Chem Toxicol. 2006;44:835–8.

    Article  CAS  PubMed  Google Scholar 

  164. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol. 2007;45:2179–205.

    Article  CAS  PubMed  Google Scholar 

  165. Jeon H, Kim H, Choi D, Kim D, Park SY, Kim YJ, Kim YM, Jung Y. Quercetin activates an angiogenic pathway, hypoxia inducible factor (HIF)-1-vascular endothelial growth factor, by inhibiting HIF-prolyl hydroxylase: a structural analysis of quercetin for inhibiting HIF-prolyl hydroxylase. Mol Pharmacol. 2007;71:1676–84.

    Article  CAS  PubMed  Google Scholar 

  166. Lamson DW, Brignall MS. Antioxidants and cancer III: quercetin. Altern Med Rev. 2000;5:196–208.

    CAS  PubMed  Google Scholar 

  167. Liu FT, Agrawal SG, Movasaghi Z, Wyatt PB, Rehman IU, Gribben JG, Newland AC, Jia L. Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib. Blood. 2008;112:3835–46.

    Article  CAS  PubMed  Google Scholar 

  168. Lugli E, Ferraresi R, Roat E, Troiano L, Pinti M, Nasi M. Quercetin inhibits lymphocyte activation and proliferation without inducing apoptosis in peripheral mononuclear cells. Leuk Res. 2009;33:140–50.

    Article  CAS  PubMed  Google Scholar 

  169. Pérez-Pastén R, Martínez-Galero E, Chamorro-Cevallos G. Quercetin and naringenin reduce abnormal development of mouse embryos produced by hydroxyurea. J Pharm Pharmacol. 2010;62:1003–9.

    Article  PubMed  CAS  Google Scholar 

  170. Vanhees K, de Bock L, Godschalk RW. Prenatal exposure to flavonoids: implication for cancer risk. Toxicol Sci. 2011;120:59–67.

    Article  CAS  PubMed  Google Scholar 

  171. Chen R, Lin J, Hong J, Han D, Addison D, Zhang, Lan R, Fu L, Z W, Lin J, Zhang W, Wang Z, Chen W, Chen C, Zhang H. Potential toxicity of quercetin: the repression of mitochondrial copy number via decreased POLG expression and excessive TFAM expression in irradiated murine bone marrow. Toxicol Rep. 2014;1:450–8.

    Article  CAS  Google Scholar 

  172. Ludwig-Müller J, Tokalov SV, Franz A, Gutzeit HO. Quercetin metabolism in vital and apoptotic human leukaemia cells. Biol Chem. 2005;386:279–83.

    Article  PubMed  CAS  Google Scholar 

  173. Sak K. Cytotoxicity of dietary flavonoids on different human cancer types. Pharmacogn Rev. 2014;8:122–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Li RF, Feng YQ, Chen JH, Ge LT, Xiao SY, Zup XL. Naringenin suppresses K562 human leukemia cell proliferation and ameliorates adriamycin-induced oxidative damage in polymorphonuclear leukocytes. Exp Ther Med. 2015;9:697–706.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Xu G, Shi H, Ren L, Gou H, Gong D, Gao X, Huang N. Enhancing the anti-colon cancer activity of quercetin by self-assembled micelles. Int J Nanomedicine. 2015;10:2051–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Moretti E, Mazzi L, Bonechi C, Salvatici MC, Iacoponi F, Rossi C, Collodel G. Effect of quercetin-loaded liposomes on induced oxidative stress in human spermatozoa. Reprod Toxicol. 2016;60:140–7.

    Article  CAS  PubMed  Google Scholar 

  177. Suksiriworapong J, Phoca K, Ngamsom S, Sripha K, Moongkarndi P, Junyaprasert VB. Comparison of poly(ε-caprolactone) chain lengths of poly(ε-caprolactone)-co-d-α-tocopheryl-poly(ethylene glycol) 1000 succinate nanoparticles for enhancement of quercetin delivery to SKBR3 breast cancer cells. Eur J Pharm Biopharm. 2016;101:15–24.

    Article  CAS  PubMed  Google Scholar 

  178. Tuli HS, Sharma AK, Sandhu SS, Kashyap D. Cordycepin: a bioactive metabolite with therapeutic potential. Life Sci. 2013;93:863–9.

    Article  CAS  PubMed  Google Scholar 

  179. Tuli HS, Kashyap D, Sharma AK, Sandhu SS. Molecular aspects of melatonin (MLT)-mediated therapeutic effects. Life Sci. 2015;135:147–57.

    Article  CAS  PubMed  Google Scholar 

  180. Ravishankar D, Watson KA, Boateng SY, Green RJ, Greco F, Osborn HM. Exploring quercetin and luteolin derivatives as antiangiogenic agents. Eur J Med Chem. 2015;97:259–74.

    Article  CAS  PubMed  Google Scholar 

  181. Sudan S, Rupasinghe HV. Antiproliferative activity of long chain acylated esters of quercetin-3-O-glucoside in hepatocellular carcinoma HepG2 cells. Exp Biol Med (Maywood). 2015;240:1452–64.

    Article  CAS  Google Scholar 

  182. Hoek-van den Hil EF, van Schothorst EM, van der Stelt I, Hollman PC, Keijer J, Rietjens IM. Quercetin tests negative for genotoxicity in transcriptome analyses of liver and small intestine of mice. Food Chem Toxicol. 2015;81:34–9.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to acknowledge Maharishi Markandeshwaar University, Mullana-Ambala, and Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh for providing the requisite facilities to complete this study. The authors are also thankful to Dr. Pawan Kumar for providing valuable suggestions for drafting the artwork of the manuscript.

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  1. Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, Punjab, 160012, India

    Dharambir Kashyap

  2. School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India

    Sonam Mittal

  3. Department of Hematology and Oncology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia

    Katrin Sak

  4. Department of Biotechnology, Maharishi Markandeshwar University, Mullana, Ambala, 133203, India

    Paavan Singhal & Hardeep Singh Tuli

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  1. Dharambir Kashyap
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Correspondence to Hardeep Singh Tuli.

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Dharambir Kashyap and Sonam Mittal contributed equally to this manuscript

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Kashyap, D., Mittal, S., Sak, K. et al. Molecular mechanisms of action of quercetin in cancer: recent advances. Tumor Biol. 37, 12927–12939 (2016). https://doi.org/10.1007/s13277-016-5184-x

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