Potential of the Flavonoid Quercetin to Prevent and Treat Cancer – Current Status of Research

Česká verze

Authors: Neuwirthová Jana; Gál Břetislav; Smilek Pavel; Urbánková Pavla
Authors place of work: Klinika otorinolaryngologie a chirurgie hlavy a krku, LF MU a FN u sv. Anny v Brně
Published in the journal: Klin Onkol 2018; 31(3): 184-190
Category: Přehledy
doi: https://doi.org/10.14735/amko2018184

Summary

Naturally occurring bioactive compounds are promising candidates to prevent and treat cancer. Quercetin is a well-known plant flavonoid that is reported to have anticancer actions in vitro and in vivo. This review focuses on the molecular mechanisms underlying the chemopreventive effect of quercetin and its therapeutic potential in oncology. Quercetin elicits biphasic, hormetic, dose-dependent effects. It acts as an antioxidant and thus elicits chemopreventive effects at low concentrations, but functions as a pro-oxidant and may therefore elicit chemotherapeutic effects at high concentrations. Quercetin has multiple intracellular molecular targets with the potential to reverse treatment resistance and affect pleiotropic signaling processes that are altered in cancer cells. Studies suggest that quercetin binds to several receptors that play important roles in carcinogenesis, regulates expression of various genes, induces epigenetic changes, and interferes with enzymes that metabolize chemical carcinogens. In addition, it also elicits anti-inflammatory and antiviral effects. The ability of quercetin to induce apoptosis of cancer cells without affecting non-cancer cells has been documented using various cell lines. Quercetin also has antiangiogenic and antimetastatic properties. When used in combination with chemotherapy and radiotherapy, quercetin can act as a sensitizer and protect non-cancer cells from the side effects of currently used cancer therapies. The safety and potential usefulness of quercetin for the prevention and treatment of cancer have been documented in both animal experiments and a phase I clinical trial. Current studies are focused on nano-formulations to overcome the low bioavailability of natural quercetin, which limits its clinical use as an antitumor agent.

Key words:
quercetin – flavonoid – chemoprevention – oxidative stress – apoptosis – antitumor agent – cancer therapy – cancer

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted: 22. 1. 2018

Accepted: 16. 4. 2018

Zdroje

1. Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer 1992; 18 (1): 1–29. doi: 10.1080/01635589209514201.

2. Gibellini L, Pinti M, Nasi M et al. Quercetin and Cancer Chemoprevention. Evidence-based Complement Alternat Med 2011; 2011: 591356. doi: 10.1093/ecam/neq053.

3. Sak K. Site-specific anticancer effects of dietary flavonoid quercetin. Nutr Cancer 2014; 66 (2): 177–193. doi: 10.1080/01635581.2014.864418.

4. Beniston RG, Campo MS. Quercetin elevates p27 (Kip1) and arrests both primary and HPV16 E6/E7 transformed human keratinocytes in G1. Oncogene 2003; 22 (35): 5504–5514.

5. Ong CS, Tran E, Nguyen TT et al. 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 (3): 727–733.

6. Ma L, Feugang JM, Konarski P et al. Growth inhibitory effects of quercetin on bladder cancer cell. Front Biosci 2006; 11: 2275–2285.

7. Russo GL, Russo M, Spagnuolo C et al. Quercetin: a pleiotropic kinase inhibitor against cancer. Cancer Treat Res 2014; 159: 185–205. doi: 10.1007/978-3-642-38007-5_11.

8. Kashyap D, Mittal S, Sak K et al. Molecular mechanisms of action of quercetin in cancer: recent advances. Tumour Biol 2016; 37 (10): 12927–12939. doi: 10.1007/s13277-016-5184-x.

9. Shan BE, Wang MX, Li RQ. Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/beta-catenin signaling pathway. Cancer Invest 2009; 27 (6): 604–612. doi: 10.1080/07357900802337191.

10. Tanigawa S, Fujii M, Hou DX. Stabilization of p53 is involved in quercetin-induced cell cycle arrest and apoptosis in HepG2 cells. Biosci Biotechnol Biochem 2008; 72 (3): 797–804. doi: 10.1271/bbb.70680.

11. Agarwal ML, Agarwal A, Taylor WR et al. p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc Natl Acad Sci USA 1995; 92 (18): 8493–8497.

12. Haghiac M, Walle T. Quercetin induces necrosis and apoptosis in SCC-9 oral cancer cells. Nutr Cancer 2005; 53 (2): 220–231. doi: 10.1207/s15327914nc5302_11.

13. Pan MH, Lai CS, Wu JC et al. Epigenetic and disease targets by polyphenols. Curr Pharm Des 2013; 19 (34): 6156–6185.

14. Slabý O. MikroRNA vstupují do klinického testování. Klin Onkol 2012; 25 (2): 139–142.

15. Yadav VR, Prasad S, Sung B et al. Targeting inflammatory pathways by triterpenoids for prevention and treatment of cancer. Toxins (Basel) 2010; 2 (10): 2428–2466. doi: 10.3390/toxins2102428.

16. Xiao X, Shi D, Liu L et al. Quercetin Suppresses Cyclooxygenase-2 Expression and Angiogenesis through Inactivation of P300 Signaling. PLoS One 2011; 6 (8): e22934. doi: 10.1371/journal.pone.0022934.

17. Raja SB, Rajendiran V, Kasinathan NK et al. Differential cytotoxic activity of Quercetin on colonic cancer cells depends on ROS generation through COX-2 expression. Food Chem Toxicol 2017; 106 (Pt A): 92–106. doi: 10.1016/j.fct.2017.05.006.

18. Nair MP, Mahajan S, Reynolds JL et al. The Flavonoid Quercetin Inhibits Proinflammatory Cytokine (Tumor Necrosis Factor Alpha) Gene Expression in Normal Peripheral Blood Mononuclear Cells via Modulation of the NF-κβ System. Clinical and Vaccine Immunology 2006; 13 (3): 319–328.

19. Zhang W, Yin G, Dai J et al. Chemoprevention by Quercetin of oral squamous cell carcinoma by suppression of the NF-κB signaling pathway in DMBA-treated hamsters. Anticancer Res 2017; 37 (8): 4041–4049. doi: 10.21873/anticanres.11789.

20. Chung S, Yao H, Caito S et al. Regulation of SIRT1 in cellular functions: role of polyphenols. Arch Biochem Biophys 2010; 501 (1): 79–90. doi: 10.1016/j.abb.2010.05.003.

21. Mendoza EE, Burd R. Quercetin as a systemic chemopreventative agent: structural and functional mechanisms. Mini Rev Med Chem 2011; 11 (14): 1216–1221.

22. Igura K, Ohta T, Kuroda Y et al. Resveratrol and quercetin inhibit angiogenesis in vitro. Cancer Lett 2001; 171 (1): 11–16.

23. Pratheeshkumar P, Budhraja A, Son Y-O et al. quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR-2 regulated AKT/mTOR/P70S6K signaling pathways. PLoS One 2012; 7 (10): e47516. doi: 10.1371/journal.pone.0047516.

24. Song W, Zhao X, Xu J et al. Quercetin inhibits angiogenesis-mediated human retinoblastoma growth by targeting vascular endothelial growth factor receptor. Oncology Letters 2017; 14 (3): 3343–3348. doi: 10.3892/ol.2017.6623.

25. Yu D, Ye T, Xiang Y et al. Quercetin inhibits epithelial–mesenchymal transition, decreases invasiveness and metastasis, and reverses IL-6 induced epithelial–mesenchymal transition, expression of MMP by inhibiting STAT3 signaling in pancreatic cancer cells. OncoTargets and therapy 2017; 10: 4719–4729. doi: 10.2147/OTT.S136840.

26. Lai WW, Hsu SC, Chueh FS et al. Quercetin inhibits migration and invasion of SAS human oral cancer cells through inhibition of NF-κB and matrix metalloproteinase-2/-9 signaling pathways. Anticancer Res 2013; 33 (5): 1941–1950.

27. Chen Y, Xiao P, Ou-Yang DS et al. 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 (8): 828–833. doi: 10.1111/j.1440-1681.2009.05158.x.

28. Tanigawa S, Fujii M, Hou DX. Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med 2007; 42 (11): 1690–1703. doi: 10.1016/j.freeradbiomed.2007.02.017.

29. Odenthal J, van Heumen BW, Roelofs HM et al. 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 (6): 856–863. doi: 10.1080/01635581.2012.700994.

30. George VC, Dellaire G, Rupasinghe HPV. Plant flavonoids in cancer chemoprevention: role in genome stability. J Nutr Biochem 2017; 45: 1–14. doi: 10.1016/j.jnutbio.2016.11.007.

31. Vargas AJ, Burd R. Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management. Nutr Rev 2010; 68 (7): 418–428. doi: 10.1111/j.1753-4887.2010.00301.x.

32. Kimura S, Warabi E, Yanagawa T et al. Essential role of Nrf2 in keratinocyte protection from UVA by quercetin. Biochem Biophys Res Commun 2009; 387 (1): 109–114. doi: 10.1016/j.bbrc.2009.06.136.

33. Pastorek M, Müller P, Vojtěšek B. Nrf2 – dve tváre regulátora antioxidačného systému. Klin Onkol 2015; 28 (Suppl 2): 26–31. doi: 10.14735/amko20152S47.

34. Min K, Ebeler SE. Quercetin inhibits hydrogen peroxide-induced DNA damage and enhances DNA repair in Caco-2 cells. Food Chem Toxicol 2009; 47 (11): 2716–2722. doi: 10.1016/j.fct.2009.07.033.

35. Mohammadi-Bardbori A, Bengtsson J, Rannug U et al. Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR). Chem Res Toxicol 2012; 25 (9): 1878–1884. doi: 10.1021/tx300 169e.

36. Bulzomi P, Galluzzo P, Bolli A et al. The pro-apoptotic effect of quercetin in cancer cell lines requires ERβ-dependent signals. J Cell Physiol 2012; 227 (5): 1891–1898. doi: 10.1002/jcp.22917.

37. Boam T. Anti-androgenic effects of flavonols in prostate cancer. Ecancermedicalscience 2015; 9: 585. doi: 10.3332/ecancer.2015.585.

38. Baby B, Antony P, Vijayan R. Interactions of quercetin with receptor tyrosine kinases associated with human lung carcinoma. Nat Prod Res 2017: 1–4. doi: 10.1080/14786419.2017.1385015.

39. Sirák I. Hátlová J, Petera J et al. Receptor pro epidermální růstový faktor a jeho úloha v radioterapii. Klin Onkol 2008; 21 (6): 338–347.

40. Caltagirone S, Ranelletti FO, Rinelli A et al. Interaction with type II estrogen binding sites and antiproliferative activity of tamoxifen and quercetin in human non-small-cell lung cancer. Am J Respir Cell Mol Biol 1997; 17 (1): 51–59. doi: 10.1165/ajrcmb.17.1.2728.

41. Piantelli M, Maggiano N, Ricci R et al. Tamoxifen and quercetin interact with type II estrogen binding sites and inhibit the growth of human melanoma cells. J Invest Dermatol 1995; 105 (2): 248–253.

42. Hansen RK, Oesterreich S, Lemieux P et al. Quercetin inhibits heat shock protein induction but not heat shock factor DNA-binding in human breast carcinoma cells. Biochem Biophys Res Commun 1997; 239 (3): 851–856. doi: 10.1006/bbrc.1997.7572.

43. Zanini C, Giribaldi G, Mandili G et al. Inhibition of heat shock proteins (HSP) expression by quercetin and differential doxorubicin sensitization in neuroblastoma and Ewing‘s sarcoma cell lines. J Neurochem 2007; 103 (4): 1344–1354. doi: 10.1111/j.1471-4159.2007.04835.x.

44. Wu W, Li R, Li X et al. Quercetin as an antiviral agent inhibits Influenza A Virus (IAV) entry. Viruses 2016; 8 (1): 6. doi: 10.3390/v8010006.

45. Lee M, Son M, Ryu E et al. Quercetin-induced apoptosis prevents EBV infection. Oncotarget 2015; 6 (14): 12603–12624. doi: 10.18632/oncotarget.3687.

46. Lee HH, Lee S, Shin YS et al. Anti-Cancer Effect of Quercetin in Xenograft Models with EBV-Associated Human Gastric Carcinoma. Molecules 2016; 21 (10): 1286. doi: 10.3390/molecules21101286.

47. Váňová B, Golais F. Onkogénny potenciál papilomavírusov. Klin onkol 2013; 26 (6): 399–403. doi: 10.14735/amko2013409.

48. Beniston RG, Campo MS. Quercetin elevates p27 (Kip1) and arrests both primary and HPV16 E6/E7 transformed human keratinocytes in G1. Oncogene 2003; 22 (35): 5504–5514. doi: 10.1038/sj.onc.1206848.

49. Beniston RG, Campo MS. HPV-18 transformed cells fail to arrest in G1 in response to quercetin treatment. Virus Res 2005; 109 (2): 203–209. doi: 10.1016/j.virusres.2004.12.002.

50. Murakami A, Ashida H, Terao J. Multitargeted cancer prevention by quercetin. Cancer Lett 2008; 269 (2): 315–325. doi: 10.1016/j.canlet.2008.03.046.

51. Priyadarsini RV, Vinothini G, Murugan RS et al. The flavonoid quercetin modulates the hallmark capabilities of hamster buccal pouch tumors. Nutr Cancer 2011; 63 (2): 218–226. doi: 10.1080/01635581.2011.523503.

52. Castillo MH, Perkins E, Campbell JH et al. The effects of the bioflavonoid quercetin on squamous cell carcinoma of head and neck origin. Am J Surg 1989; 158 (4): 351–355.

53. Warren CA, Paulhill KJ, Davidson LA et al. Quercetin may suppress rat aberrant crypt foci formation by suppressing inflammatory mediators that influence proliferation and apoptosis. J Nutr 2009; 139 (1): 101–105. doi: 10.3945/jn.108.096271.

54. Ali H, Dixit S. Quercetin attenuates the development of 7, 12-dimethyl benz (a) anthracene (DMBA) and croton oil-induced skin cancer in mice. J Biomed Res 2015; 29 (2): 139–144. doi: 10.7555/JBR.29.20130025.

55. Kamaraj S, Vinodhkumar R, Anandakumar P et al. The effects of quercetin on antioxidant status and tumor markers in the lung and serum of mice treated with benzo (a) pyrene. Biol Pharm Bull 2007; 30 (12): 2268–2273.

56. Jin NZ, Zhu YP, Zhou JW et al. Preventive effects of quercetin against benzo[a]pyrene-induced DNA damages and pulmonary precancerous pathologic changes in mice. Basic Clin Pharmacol Toxicol 2006; 98 (6): 593–598. doi: 10.1111/j.1742-7843.2006.pto_382.x

57. Ferry DR, Smith A, Malkhandi J et al. Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 1996; 2 (4): 659–668.

58. Ekstrom AM, Serafini M, Nyren O et al. Dietary quercetin intake and risk of gastric cancer: Results from a population-based study in Sweden. Ann Oncol 2011; 22 (2): 438–443. doi: 10.1093/annonc/mdq390.

59. Theodoratou E, Kyle J, Cetnarskyj R et al. Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 2007; 16 (4): 684–693. doi: 10.1158/1055-9965.EPI-06-0785.

60. Lam TK, Rotunno M, Lubin JH et al. Dietary quercetin, quercetin-gene interaction, metabolic gene expression in lung tissue and lung cancer risk. Carcinogenesis 2010; 31 (4): 634–642. doi: 10.1093/carcin/bgp334.

61. Rozenfeld LG, Abyzov RA, Bozhko GT. The possibilities of protection against local radiation injuries in ORL-oncologic patients. Vestn Otorinolaryngol 1990; 2: 56–58.

62. Brito AF, Ribeiro M, Abrantes AM et al. Quercetin in cancer treatment, alone or in combination with conventional therapeutics? Curr Med Chem 2015; 22 (26): 3025–3039.

63. Miles SL, McFarland M, Niles RM. Molecular and physiological actions of quercetin: need for clinical trials to assess its benefits in human disease. Nutr Rev 2014; 72 (11): 720–734. doi: 10.1111/nure.12152.

64. Daker M, Ahmad M, Khoo AS. Quercetin-induced inhibition and synergistic activity with cisplatin – a chemotherapeutic strategy for nasopharyngeal carcinoma cells. Cancer Cell Int 2012; 12 (1): 34. doi: 10.1186/1475-2867-12-34.

65. Kuhar M, Imran S, Sigh N. Curcumin and Quercetin combined with Cisplatin to induce apoptosis in human laryngeal carcinoma Hep-2 cells through the mitochondrial pathway. Journal of Cancer Molecules 2007; 3: 121–128.

66. Scambia G, Ranelletti FO, Benedetti Panici P et al. Inhibitory effect of quercetin on primary ovarian and endometrial cancers and synergistic activity with cis-diamminedichloroplatinum (II). Gynecol Oncol 1992; 45 (1): 13–19.

67. Sanchez-Gonzalez PD, Lopez-Hernandez FJ, Perez-Barriocanal F et al. Quercetin reduces cisplatin nephrotoxicity in rats without compromising its anti-tumour activity. Nephrol Dial Transplant 2011; 26 (11): 3484–3495. doi: 10.1093/ndt/gfr195.

68. Chen C, Zhou J, Ji C. Quercetin: a potential drug to reverse multidrug resistance. Life Sci 2010; 87 (11–12): 333–338. doi: 10.1016/j.lfs.2010.07.004.

69. Lee J, Mitchell AE. Pharmacokinetics of quercetin absorption from apples and onions in healthy humans. J Agric Food Chem 2012; 60 (15): 3874–3881. doi: 10.1021/jf3001857.

70. Lamson DW, Brignall MS. Antioxidants and cancer, part 3: quercetin. Altern Med Rev 2000; 5 (3): 196–208.

71. Nielsen SE, Kall M, Justesen U et al. Human absorption and excretion of flavonoids after broccoli consumption. Cancer Lett 1997; 114 (1–2): 173–174.

72. Hollman PC, van Trijp JM, Mengelers MJ et al. Bioavailibility of diatery antioxidant flavanol quercetin in man. Cancer Lett 1997; 114 (1–2): 139–140.

73. Jeong JH, An JY, Kwon YT et al. Effects of low dose quercetin: Cancer cell-specific inhibition of cell cycle progression. J Cell Biochem 2009; 106 (1): 73–82. doi: 10.1002/jcb.21977.

74. Matsuo M, Sasaki N, Saga K et al. Cytotoxicity of flavonoids toward cultured normal human cells. Biol Pharm Bull 2005; 28 (2): 253–259.

75. Caltagirone S, Rossi C, Poggi A et al. Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer 2000; 87 (4): 595–600.

76. Men K, Duan X, Wei XW et al. Nanoparticle-delivered quercetin for cancer therapy. Anticancer Agents Med Chem 2014; 14 (6): 826–832.

77. Davatgaran-Taghipour Y, Masoomzadeh S, Farzaei MH et al. Polyphenol nanoformulations for cancer therapy: experimental evidence and clinical perspective. Int J Nanomedicine 2017; 12: 2689–2702. doi: 10.2147/IJN.S131973.