Quercetin as an Emerging Anti-Melanoma Agent: A Four-Focus Area Therapeutic Development Strategy

Frontiers in Nutrition

Volumn 3, Issue , 2016, Pages

  Harris, Zoey ^a   Donovan, Micah G ^a   Branco, Gisele Morais ^a   Limesand, Kirsten H ^a   Burd, Randy ^a  

^a UNIVERSITY OF ARIZONA   (United States)

Author keywords

melanoma; quercetin

Indexed keywords

EID: 85021996121     PISSN: None     EISSN: 2296861X     Source Type: Journal    
DOI: 10.3389/fnut.2016.00048     Document Type: Review

References (140)

1. American Cancer Society. Cancer Facts & Figures 2016. (2016). p. 1–9.
2. Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature (2007) 445:851–7.10.1038/nature0566117314971
3. Cummins DL, Cummins JM, Pantle H, Silverman MA, Leonard AL, Chanmugam A. Cutaneous malignant melanoma. Mayo Clin Proc (2006) 81:500–7.10.4065/81.4.50016610570
4. Balch CM, Gershenwald JE, Soong S-J, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol (2009) 27:6199–206.10.1200/jco.2009.23.479919917835
5. Weber J, Thompson JA, Hamid O, Minor D, Amin A, Ron I, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res (2009) 15:5591–8.10.1158/1078-0432.ccr-09-102419671877
6. O’day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol (2010) 21:1712–7.10.1093/annonc/mdq01320147741
7. Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol (2010) 11:155–64.10.1016/s1470-2045(09)70334-120004617
8. Thangasamy T, Sittadjody S, Lanza-Jacoby S, Wachsberger PR, Limesand KH, Burd R. Quercetin selectively inhibits bioreduction and enhances apoptosis in melanoma cells that overexpress tyrosinase. Nutr Cancer (2007) 59:258–68.10.1080/0163558070149954518001220
9. Vargas AJ, Burd R. Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management. Nutr Rev (2010) 68:418–28.10.1111/j.1753-4887.2010.00301.x20591109
10. Kubo I, Nitoda T, Nihei K-I. Effects of quercetin on mushroom tyrosinase and B16-F10 melanoma cells. Molecules (2007) 12:1045–56.10.3390/1205104517873839
11. Metodiewa D, Jaiswal AK, Cenas N, Dickancaité E, Segura-Aguilar J. Quercetin may act as a cytotoxic prooxidant after its metabolic activation to semiquinone and quinoidal product. Free Radic Biol Med (1999) 26:107–16.10.1016/s0891-5849(98)00167-19890646
12. Cichorek M, Wachulska M, Stasiewicz A, Tymińska A. Skin melanocytes: biology and development. Postepy Dermatol Alergol (2013) 30:30–41.10.5114/pdia.2013.33376
13. Sullivan RJ, Fisher DE. Understanding the biology of melanoma and therapeutic implications. Hematol Oncol Clin North Am (2014) 28:437–53.10.1016/j.hoc.2014.02.00724880940
14. Herlyn M, Thurin J, Balaban G, Bennicelli JL, Herlyn D, Elder DE, et al. Characteristics of cultured human melanocytes isolated from different stages of tumor progression. Cancer Res (1985) 45:5670–6.10.1007/978-1-4613-1751-7_1
15. Liu J, Fukunaga-Kalabis M, Li L, Herlyn M. Developmental pathways activated in melanocytes and melanoma. Arch Biochem Biophys (2014) 563:13–21.10.1016/j.abb.2014.07.02325109840
16. Quaglino P, Osella-Abate S, Cappello N, Ortoncelli M, Nardò T, Fierro MT, et al. Prognostic relevance of baseline and sequential peripheral blood tyrosinase expression in 200 consecutive advanced metastatic melanoma patients. Melanoma Res (2007) 17:75–82.10.1097/cmr.0b013e328054c66717496782
17. Chin L, Garraway LA, Fisher DE. Malignant melanoma: genetics and therapeutics in the genomic era. Genes Dev (2006) 20:2149–82.10.1101/gad.143720616912270
18. Miller AJ, Mihm MC. Melanoma. N Engl J Med (2006) 355:51–65.10.1056/nejmra052166
19. Tsao H, Chin L, Garraway LA, Fisher DE. Melanoma: from mutations to medicine. Genes Dev (2012) 26:1131–55.10.1101/gad.191999.11222661227
20. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature (2002) 417:949–54.10.1038/nature0076612068308
21. Garnett MJ, Marais R. Guilty as charged: B-RAF Is a human oncogene. Cancer Cell (2004) 6:313–9.10.1016/j.ccr.2004.09.02215488754
22. Houben R, Becker JC, Kappel A, Terheyden P, Bröcker EB, Goetz R, et al. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog (2004) 3:6.10.1186/1477-3163-3-615046639
23. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell (2004) 116:855–67.10.1016/S0092-8674(04)00215-615035987
24. Wellbrock C, Ogilvie L, Hedley D, Karasarides M, Martin J, Niculescu-Duvaz D, et al. V599EB-RAF is an oncogene in melanocytes. Cancer Res (2004) 64:2338–42.10.1158/0008-5472.can-03-343315059882
25. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med (2012) 367:107–14.10.1056/nejmoa120342122663011
26. Kwong LN, Davies MA. Navigating the therapeutic complexity of PI3K pathway inhibition in melanoma. Clin Cancer Res (2013) 19:5310–9.10.1158/1078-0432.ccr-13-014224089444
27. Barbacid M. Ras genes. Annu Rev Biochem (1987) 56:779–827.10.1146/annurev.biochem.56.1.779
28. Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P, et al. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell (1997) 89:457–67.10.1016/s0092-8674(00)80226-39150145
29. Davies MA, Fox PS, Papadopoulos NE, Bedikian AY, Hwu W-J, Lazar AJ, et al. Phase I study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma. Clin Cancer Res (2012) 18:1120–8.10.1158/1078-0432.ccr-11-243622223528
30. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE, Jr et al. BrafV600E cooperates with Pten loss to induce metastatic melanoma. Nat Genet (2009) 41:544–52.10.1038/ng.356
31. Nickoloff BJ, Osborne BA, Miele L. Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents. Oncogene (2003) 22:6598–608.10.1038/sj.onc.120675814528285
32. Asnaghi L, Ebrahimi KB, Schreck KC, Bar EE, Coonfield ML, Bell WR, et al. Notch signaling promotes growth and invasion in uveal melanoma. Clin Cancer Res (2012) 18:654–65.10.1158/1078-0432.ccr-11-140622228632
33. Barth A, Wanek LA, Morton DL. Prognostic factors in 1,521 melanoma patients with distant metastases. J Am Coll Surg (1995) 181:193–201.7670677
34. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med (2010) 363:1290–1290.10.1056/nejmx100063
35. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med (2011) 364:2507–16.10.1056/NEJMoa110378221639808
36. Hauschild A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet (2012) 380:358–65.10.1016/s0140-6736(12)60868-x22735384
37. Maverakis E, Cornelius L, Bowen G, Phan T, Patel F, Fitzmaurice S, et al. Metastatic melanoma – a review of current and future treatment options. Acta Derm Venereol (2015) 95:516–24.10.2340/00015555-2035
38. Boly R, Gras T, Lamkami T, Guissou P, Serteyn D, Kiss R, et al. Quercetin inhibits a large panel of kinases implicated in cancer cell biology. Int J Oncol (2011) 38:833–42.10.3892/ijo.2010.89021206969
39. Harborne JB. Nature, distribution and function of plant flavonoids. Prog Clin Biol Res (1986) 213:15–24.
40. Aherne SA, O’brien NM. Protection by the flavonoids myricetin, quercetin, and rutin against hydrogen peroxide-induced DNA damage in caco-2 and Hep G2 cells. Nutr Cancer (1999) 34:160–6.10.1207/s15327914nc3402_610578483
41. O’Prey J, Brown J, Fleming J, Harrison PR. Effects of dietary flavonoids on major signal transduction pathways in human epithelial cells. Biochem Pharmacol (2003) 66:2075–88.10.1016/j.bcp.2003.07.00714609732
42. Harwood M, Danielewska-Nikiel B, Borzelleca J, Flamm G, Williams G, Lines T. 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) 45:2179–205.10.1016/j.fct.2007.05.015
43. Spagnuolo C, Russo M, Bilotto S, Tedesco I, Laratta B, Russo GL. Dietary polyphenols in cancer prevention: the example of the flavonoid quercetin in leukemia. Ann N Y Acad Sci (2012) 1259:95–103.10.1111/j.1749-6632.2012.06599.x22758641
44. Hertog MG, Kromhout D, Aravanis C, Blackburn H, Buzina R, Fidanza F, et al. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch Intern Med (1995) 155:381–6.10.1001/archinte.1995.004300400530067848021
45. Vargas AJ, Sittadjody S, Thangasamy T, Mendoza EE, Limesand KH, Burd R. Exploiting tyrosinase expression and activity in melanocytic tumors: quercetin and the central role of p53. Integr Cancer Ther (2010) 10:328–40.10.1177/1534735410391661
46. Gugler R, Leschik M, Dengler HJ. Disposition of quercetin in man after single oral and intravenous doses. Eur J Clin Pharmacol (1975) 9:229–34.10.1007/bf006140221233267
47. Moon YJ, Wang L, Dicenzo R, Morris ME. Quercetin pharmacokinetics in humans. Biopharm Drug Dispos (2008) 29:205–17.10.1002/bdd.60518241083
48. Sampson L, Rimm E, Hollman PC, Vries JHD, Katan MB. Flavonol and flavone intakes in US health professionals. J Am Diet Assoc (2002) 102:1414–20.10.1016/s0002-8223(02)90314-712396158
49. Murota K, Terao J. Antioxidative flavonoid quercetin: implication of its intestinal absorption and metabolism. Arch Biochem Biophys (2003) 417:12–7.10.1016/s0003-9861(03)00284-412921774
50. Németh K, Plumb GW, Berrin J-G, Juge N, Jacob R, Naim HY, et al. Deglycosylation by small intestinal epithelial cell beta-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur J Nutr (2003) 42:29–42.10.1007/s00394-003-0397-312594539
51. Day AJ, Dupont M, Ridley S, Rhodes M, Rhodes MJ, Morgan MR, et al. Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver β-glucosidase activity. FEBS Lett (1998) 436:71–5.10.1016/s0014-5793(98)01101-6
52. Crespy V, Morand C, Manach C, Besson C, Demigne C, Remesy C. Part of quercetin absorbed in the small intestine is conjugated and further secreted in the intestinal lumen. Am J Physiol (1999) 277:120–6.10409158
53. Graf BA, Ameho C, Dolnikowski GG, Milbury PE, Chen CY, Blumberg JB. Rat gastrointestinal tissues metabolize quercetin. J Nutr (2006) 136:39–44.16365056
54. Egert S, Wolframm S, Bosy-Westphai A, Boesch-Saadatmandi C, Wagner AE, Frank J, et al. Daily quercetin supplementation dose-dependently increases plasma quercetin concentrations in healthy humans. J Nutr (2008) 138:1615–21.18716159
55. Piskula MK, Németh K. Food content, processing, absorption and metabolism of onion flavonoids. Crit Rev Food Sci Nutr (2007) 47:397–409.10.1080/1040839060084629117457724
56. Graefe EU, Wittig J, Mueller S, Riethling A-K, Uehleke B, Drewelow B, et al. Pharmacokinetics and bioavailability of quercetin glycosides in humans. J Clin Pharmacol (2001) 41:492–9.10.1177/0091270012201036611361045
57. Lesser S, Cermak R, Wolffram S. Bioavailability of quercetin in pigs is influenced by the dietary fat content. J Nutr (2004) 134:1508–11.15173420
58. Silberberg M, Morand C, Manach C, Scalbert A, Remesy C. Co-administration of quercetin and catechin in rats alters their absorption but not their metabolism. Life Sci (2005) 77:3156–67.10.1016/j.lfs.2005.03.03315979103
59. Eitsuka T, Tatewaki N, Nishida H, Nakagawa K, Miyazawa T. Synergistic anticancer effect of tocotrienol combined with chemotherapeutic agents or dietary components: a review. Int J Mol Sci (2016) 17:1605.10.3390/ijms1710160527669218
60. Zhou Y, Zheng J, Li Y, Xu D-P, Li S, Chen Y-M, et al. Natural polyphenols for prevention and treatment of cancer. Nutrients (2016) 8:515.10.3390/nu8080515
61. Morand C, Crespy V, Manach C, Besson C, Demigné C, Rémésy C. Plasma metabolites of quercetin and their antioxidant properties. Am J Physiol (1998) 275:R212–9.
62. Omar K, Grant MH, Henderson C, Watson DG. The complex degradation and metabolism of quercetin in rat hepatocyte incubations. Xenobiotica (2014) 44:1074–82.10.3109/00498254.2014.93203224957985
63. Horton JA, Li F, Chung EJ, Hudak K, White A, Krausz K, et al. Quercetin inhibits radiation-induced skin fibrosis. Radiat Res (2013) 180:205–15.10.1667/rr3237.123819596
64. Cai X, Fang Z, Dou J, Yu A, Zhai G. Bioavailability of quercetin: problems and promises. Curr Med Chem (2013) 20:2572–82.10.2174/0929867311320999012023514412
65. Kawabata K, Mukai R, Ishisaka A. Quercetin and related polyphenols: new insights and implications for their bioactivity and bioavailability. Food Funct (2015) 6:1399–417.10.1039/c4fo01178c25761771
66. Biasutto L, Mattarei A, Sassi N, Azzolini M, Romio M, Paradisi C, et al. Improving the efficacy of plant polyphenols. Anticancer Agents Med Chem (2014) 14:1332–42.10.2174/187152061466614062715005424975033
67. Wang L, Tu Y-C, Lian T-W, Hung J-T, Yen J-H, Wu M-J. Distinctive antioxidant and antiinflammatory effects of flavonols. J Agric Food Chem (2006) 54:9798–804.10.1021/jf062071917177504
68. Rice-Evans CA, Miller NJ, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med (1996) 20:933–56.10.1016/0891-5849(95)02227-98743980
69. Nam JS, Sharma A, Nguyen L, Chakraborty C, Sharma G, Lee S-S. Application of bioactive quercetin in oncotherapy: from nutrition to nanomedicine. Molecules (2016) 21:108.10.3390/molecules2101010826797598
70. Dhalla NS, Temsah RM, Netticadan T. Role of oxidative stress in cardiovascular diseases. J Hypertens (2000) 18:655–73.10.1097/00004872-200018060-00002
71. Uttara B, Singh A, Zamboni P, Mahajan R. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol (2009) 7:65–74.10.2174/15701590978760282319721819
72. Reddy VP, Zhu X, Perry G, Smith MA. Oxidative stress in diabetes and Alzheimer’s disease. J Alzheimers Dis (2009) 16:763–74.10.3233/JAD-2009-1013
73. Locatelli F, Canaud B, Eckardt K-U, Stenvinkel P, Wanner C, Zoccali C. Oxidative stress in end-stage renal disease: an emerging threat to patient outcome. Nephrol Dial Transplant (2003) 18:1272–80.10.1093/ndt/gfg07412808161
74. Khansari N, Shakiba Y, Mahmoudi M. Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat Inflamm Allergy Drug Discov (2009) 3:73–80.10.2174/18722130978715837119149749
75. Ranelletti FO, Maggiano N, Serra FG, Ricci R, Larocca LM, Lanza P, et al. Quercetin inhibits p21-RAS expression in human colon cancer cell lines and in primary colorectal tumors. Int J Cancer (2000) 85:438.10.1002/(sici)1097-0215(20000201)85:33.3.co;2-610652438
76. Tanigawa S, Fujii M, Hou D-X. Stabilization of p53 is involved in quercetin-induced cell cycle arrest and apoptosis in HepG2 cells. Biosci Biotechnol Biochem (2008) 72:797–804.10.1271/bbb.7068018323654
77. Soengas MS, Lowe SW. Apoptosis and melanoma chemoresistance. Oncogene (2003) 22:3138–51.10.1038/sj.onc.1206454
78. Awad HM, Boersma MG, Vervoort J, Rietjens IM. Peroxidase-catalyzed formation of quercetin quinone methide–glutathione adducts. Arch Biochem Biophys (2000) 378:224–33.10.1006/abbi.2000.1832
79. Wätjen W, Michels G, Steffan B, Niering P, Chovolou Y, Kampkötter A, et al. Low concentrations of flavonoids are protective in rat H4IIE cells whereas high concentrations cause DNA damage and apoptosis. J Nutr (2005) 135:525–31.15735088
80. Tandler N, Mosch B, Pietzsch J. Protein and non-protein biomarkers in melanoma: a critical update. Amino Acids (2012) 43:2203–30.10.1007/s00726-012-1409-523053020
81. Boyle JL, Haupt HM, Stern JB, Multhaupt HA. Tyrosinase expression in malignant melanoma, desmoplastic melanoma, and peripheral nerve tumors. Arch Pathol Lab Med (2002) 126:2.10.1043/0003-9985(2002)1262.0.CO
82. Drexler I, Antunes E, Schmitz M, Wölfel T, Huber C, Erfle V, et al. Modified vaccinia virus Ankara for delivery of human tyrosinase as melanoma-associated antigen: induction of tyrosinase- and melanoma-specific human leukocyte antigen A*0201-restricted cytotoxic T cells in vitro and in vivo. Cancer Res (1999) 59:4955–63.10519409
83. Riley PA, Cooksey CJ, Johnson CI, Land EJ, Latter AM, Ramsden CA. Melanogenesis-targeted anti-melanoma pro-drug development: effect of side-chain variations on the cytotoxicity of tyrosinase-generated ortho-quinones in a model screening system. Eur J Cancer (1997) 33:135–43.10.1016/s0959-8049(96)00340-19071913
84. Li J, Lee B, Lee AS. Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. J Biol Chem (2006) 281:7260–70.10.1074/jbc.m50986820016407291
85. Tanigawa S, Fujii M, Hou D. Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med (2007) 42:1690–703.10.1016/j.freeradbiomed.2007.02.01717462537
86. Granado-Serrano AB, Martín MA, Bravo L, Goya L, Ramos S. Quercetin modulates Nrf2 and glutathione-related defenses in HepG2 cells: involvement of p38. Chem Biol Interact (2012) 195:154–64.10.1016/j.cbi.2011.12.00522197970
87. 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) 2016:1–6.10.1155/2016/217327526942188
88. Ajit D, Simonyi A, Li R, Chen Z, Hannink M, Fritsche KL, et al. Phytochemicals and botanical extracts regulate NF-κB and Nrf2/ARE reporter activities in DI TNC1 astrocytes. Neurochem Int (2016) 97:49–56.10.1016/j.neuint.2016.05.00427166148
89. Chaiprasongsuk A, Onkoksoong T, Pluemsamran T, Limsaengurai S, Panich U. Photoprotection by dietary phenolics against melanogenesis induced by UVA through Nrf2-dependent antioxidant responses. Redox Biol (2016) 8:79–90.10.1016/j.redox.2015.12.00626765101
90. Suzuki T, Motohashi H, Yamamoto M. Toward clinical application of the Keap1–Nrf2 pathway. Trends Pharmacol Sci (2013) 34:340–6.10.1016/j.tips.2013.04.005
91. Asher G, Bercovich Z, Tsvetkov P, Shaul Y, Kahana C. 20S proteasomal degradation of ornithine decarboxylase Is regulated by NQO1. Mol Cell (2005) 17:645–55.10.1016/j.molcel.2005.01.02015749015
92. Asher G, Lotem J, Kama R, Sachs L, Shaul Y. NQO1 stabilizes p53 through a distinct pathway. Proc Natl Acad Sci U S A (2002) 99:3099–104.10.1073/pnas.05270679911867746
93. Asher G, Lotem J, Cohen B, Sachs L, Shaul Y. Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. Proc Natl Acad Sci U S A (2001) 98:1188–93.10.1073/pnas.98.3.118811158615
94. Asher G, Lotem J, Sachs L, Kahana C, Shaul Y. Mdm-2 and ubiquitin-independent p53 proteasomal degradation regulated by NQO1. Proc Natl Acad Sci U S A (2002) 99:13125–30.10.1073/pnas.20248049912232053
95. Asher G, Lotem J, Tsvetkov P, Reiss V, Sachs L, Shaul Y. p53 hot-spot mutants are resistant to ubiquitin-independent degradation by increased binding to NAD(P)H:quinone oxidoreductase 1. Proc Natl Acad Sci U S A (2003) 100:15065–70.10.1073/pnas.243632910014634213
96. Asher G, Lotem J, Sachs L, Shaul Y. p53-dependent apoptosis and NAD(P)H:quinone oxidoreductase 1. Methods Enzymol (2004) 382:278–93.10.1016/s0076-6879(04)82016-0
97. Anwar A, Dehn D, Siegel D, Kepa JK, Tang LJ, Pietenpol JA, et al. Interaction of human NAD(P)H:quinone oxidoreductase 1 (NQO1) with the tumor suppressor protein p53 in cells and cell-free systems. J Biol Chem (2003) 278:10368–73.10.1074/jbc.m21198120012529318
98. Lu M, Miller P, Lu X. Restoring the tumour suppressive function of p53 as a parallel strategy in melanoma therapy. FEBS Lett (2014) 588:2616–21.10.1016/j.febslet.2014.05.00824844434
99. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, et al. An Nrf2/Small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun (1997) 236:313–22.10.1006/bbrc.1997.69439240432
100. Nioi P, Mcmahon M, Itoh K, Yamamoto M, Hayes JD. Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence. Biochem J (2003) 374:337–48.10.1042/bj2003075412816537
101. Dinkova-Kostova AT, Holtzclaw WD, Wakabayashi N. Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Biochemistry (2005) 44:6889–99.10.1021/bi047434h15865434
102. Ogura T, Tong KI, Mio K, Maruyama Y, Kurokawa H, Sato C, et al. Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. Proc Natl Acad Sci U S A (2010) 107:2842–7.10.1073/pnas.091403610720133743
103. Tong KI, Padmanabhan B, Kobayashi A, Shang C, Hirotsu Y, Yokoyama S, et al. Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol Cell Biol (2007) 27:7511–21.10.1128/mcb.00753-0717785452
104. Rius M, Lyko F. Epigenetic cancer therapy: rationales, targets and drugs. Oncogene (2012) 31:4257–65.10.1038/onc.2011.60122179827
105. Sarkar S, Horn G, Moulton K, Oza A, Byler S, Kokolus S, et al. Cancer development, progression, and therapy: an epigenetic overview. Int J Mol Sci (2013) 14:21087–113.10.3390/ijms14102108724152442
106. Marzese DM, Hoon DS. Emerging technologies for studying DNA methylation for the molecular diagnosis of cancer. Expert Rev Mol Diagn (2015) 15:647–64.10.1586/14737159.2015.102719425797072
107. Lee WJ, Shim JY, Zhu BT. Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol Pharmacol (2005) 68:1018–30.10.1124/mol.104.00836716037419
108. Sharma V, Kumar L, Mohanty SK, Maikhuri JP, Rajender S, Gupta G. Sensitization of androgen refractory prostate cancer cells to anti-androgens through re-expression of epigenetically repressed androgen receptor – synergistic action of quercetin and curcumin. Mol Cell Endocrinol (2016) 431:12–23.10.1016/j.mce.2016.04.024
109. Tan S, Wang C, Lu C, Zhao B, Cui Y, Shi X, et al. Quercetin is able to demethylate the p16INK4a gene promoter. Chemotherapy (2009) 55:6–10.10.1159/00016638318974642
110. Zheng NG, Wang JL, Yang SL, Wu JL. Aberrant epigenetic alteration in Eca9706 cells modulated by nanoliposomal quercetin combined with butyrate mediated via epigenetic-NF-κB signaling. Asian Pac J Cancer Prev (2014) 15(11):4539–43.10.7314/APJCP.2014.15.11.4539
111. Lee WJ, Chen YR, Tseng TH. Quercetin induces FasL-related apoptosis, in part, through promotion of histone H3 acetylation in human leukemia HL-60 cells. Oncol Rep (2011) 25:583–91.10.3892/or.2010.109721165570
112. Bishayee K, Khuda-Bukhsh AR, Huh S-O. PLGA-Loaded gold-nanoparticles precipitated with quercetin downregulate HDAC-Akt activities controlling proliferation and activate p53-ROS crosstalk to induce apoptosis in hepatocarcinoma cells. Mol Cells (2015) 38:518–27.10.14348/molcells.2015.233925947292
113. Boesch-Saadatmandi C, Loboda A, Wagner AE, Stachurska A, Jozkowicz A, Dulak J, et al. Effect of quercetin and its metabolites isorhamnetin and quercetin-3-glucuronide on inflammatory gene expression: role of miR-155. J Nutr Biochem (2011) 22:293–9.10.1016/j.jnutbio.2010.02.00820579867
114. Boesch-Saadatmandi C, Wagner AE, Wolffram S, Rimbach G. Effect of quercetin on inflammatory gene expression in mice liver in vivo – role of redox factor 1, miRNA-122 and miRNA-125b. Pharmacol Res (2012) 65:523–30.10.1016/j.phrs.2012.02.007
115. Milenkovic D, Deval C, Gouranton E, Landrier J-F, Scalbert A, Morand C, et al. Modulation of miRNA expression by dietary polyphenols in apoE deficient mice: a new mechanism of the action of polyphenols. PLoS One (2012) 7:e29837.10.1371/journal.pone.002983722253797
116. Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet (1998) 19:219–20.10.1038/890
117. Sharpless E, Chin L. The INK4a/ARF locus and melanoma. Oncogene (2003) 22:3092–8.10.1038/sj.onc.120646112789286
118. Burd R, Panayi ND, Breshears ES, Mendoza EE. Aberrant death pathways in melanoma. In: Davids L, editor. Recent Advances in the Biology, Therapy and Management of Melanoma. INTECH Open Access Publisher (2013). Available from: http://www.intechopen.com/books/recent-advances-in-the-biology-therapy-and-management-of-melanoma/aberrant-death-pathways-in-melanoma
119. Venza M, Visalli M, Biondo C, Lentini M, Catalano T, Teti D, et al. Epigenetic regulation of p14ARF and p16INK4A expression in cutaneous and uveal melanoma. Biochim Biophys Acta (2015) 1849:247–56.10.1016/j.bbagrm.2014.12.00425497382
120. Jonsson A, Tuominen R, Grafström E, Hansson J, Egyhazi S. High frequency of p16INK4A promoter methylation in NRAS-mutated cutaneous melanoma. J Invest Dermatol (2010) 130:2809–17.10.1038/jid.2010.216
121. Unamuno BD, Palanca S, Botella R. Update on melanoma epigenetics. Curr Opin Oncol (2015) 27:420–6.10.1097/cco.000000000000021726197354
122. Galdieri L, Vancura A. Acetyl-CoA carboxylase regulates global histone acetylation. J Biol Chem (2012) 287:23865–76.10.1074/jbc.m112.380519
123. Libra M, Malaponte G, Navolanic PM, Gangemi P, Bevelacqua V, Proietti L, et al. Analysis of BRAF mutation in primary and metastatic melanoma. Cell Cycle (2005) 4:1382–4.10.4161/cc.4.10.202616096377
124. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature (2010) 468:973–7.10.1038/nature0962621107323
125. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol (2011) 29:3085–96.10.1200/jco.2010.33.231221383288
126. Shi H, Hong A, Kong X, Koya RC, Song C, Moriceau G, et al. A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov (2014) 4:69–79.10.1158/2159-8290.cd-13-027924265152
127. Rafiq RA, Quadri A, Nazir LA, Peerzada K, Ganai BA, Tasduq SA. A potent inhibitor of Phosphoinositide 3-Kinase (PI3K) and mitogen activated protein (MAP) kinase signalling, quercetin (3,3’,4’0.5,7-pentahydroxyflavone) promotes cell death in ultraviolet (UV)-B-irradiated B16F10 melanoma cells. PLoS One (2015) 10:1–20.10.1371/journal.pone.0131253
128. Sun ZJ, Chen G, Hu X, Zhang W, Liu Y, Zhu L-X, et al. Activation of PI3K/Akt/IKK-alpha/NF-kappaB signaling pathway is required for the apoptosis-evasion in human salivary adenoid cystic carcinoma: its inhibition by quercetin. Apoptosis (2010) 15:850–63.10.1007/s10495-010-0497-520386985
129. Pozsgai E, Bellyei S, Cseh A, Boronkai A, Racz B, Szabo A, et al. Quercetin increases the efficacy of glioblastoma treatment compared to standard chemoradiotherapy by the suppression of PI-3-Kinase-Akt pathway. Nutr Cancer (2013) 65:1059–66.10.1080/01635581.2013.81029124032376
130. Song NR, Chung M-Y, Kang NJ, Seo SG, Jang TS, Lee HJ, et al. Quercetin suppresses invasion and migration of H-Ras-transformed MCF10A human epithelial cells by inhibiting phosphatidylinositol 3-kinase. Food Chem (2014) 142:66–71.10.1016/j.foodchem.2013.07.00224001813
131. Hu J, Wang J, Wang G, Yao Z, Dang X. Pharmacokinetics and antitumor efficacy of DSPE-PEG2000 polymeric liposomes loaded with quercetin and temozolomide: analysis of their effectiveness in enhancing the chemosensitization of drug-resistant glioma cells. Int J Mol Med (2016) 37:690–702.10.3892/ijmm.2016.245826782731
132. Kumari A, Yadav SK, Pakade YB, Singh B, Yadav SC. Development of biodegradable nanoparticles for delivery of quercetin. Colloids Surf B Biointerfaces (2010) 80:184–92.10.1016/j.colsurfb.2010.06.00220598513
133. Sahoo NG, Kakran M, Shaal LA, Li L, Müller RH, Pal M, et al. Preparation and characterization of quercetin nanocrystals. J Pharm Sci (2011) 100:2379–90.10.1002/jps.2244621491450
134. Tran TH, Guo Y, Song D, Bruno RS, Lu X. Quercetin-containing self-nanoemulsifying drug delivery system for improving oral bioavailability. J Pharm Sci (2014) 103:840–52.10.1002/jps.2385824464737
135. Lockhart JN, Stevens DM, Beezer DB, Kravitz A, Harth E. Dual drug delivery of tamoxifen and quercetin: regulated metabolism for anticancer treatment with nanosponges. J Control Release (2015) 220:751–7.10.1016/j.jconrel.2015.08.05226344396
136. Pimple S, Manjappa AS, Ukawala M, Murthy RS. PLGA nanoparticles loaded with etoposide and quercetin dihydrate individually: in vitro cell line study to ensure advantage of combination therapy. Cancer Nanotechnol (2012) 3:25–36.10.1007/s12645-012-0027-y26069494
137. Li N, Sun C, Zhou B, Xing H, Ma D, Chen G, et al. Low concentration of quercetin antagonizes the cytotoxic effects of anti-neoplastic drugs in ovarian cancer. PLoS One (2014) 9:e100314.10.1371/journal.pone.010031424999622
138. Milenkovic D, Jude B, Morand C. miRNA as molecular target of polyphenols underlying their biological effects. Free Radic Biol Med (2013) 64:40–51.10.1016/j.freeradbiomed.2013.05.04623751562
139. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell (2004) 116:281–97.10.1016/S0092-8674(04)00045-514744438
140. Lam TK, Shao S, Zhao Y, Marincola F, Pesatori A, Bertazzi PA, et al. Influence of quercetin-rich food intake on microRNA expression in lung cancer tissues. Cancer Epidemiol Biomarkers Prev (2012) 21:2176–84.10.1158/1055-9965.epi-12-074523035181