The AAPS Journal

, 20:19 | Cite as

In Vitro-In Vivo Dose Response of Ursolic Acid, Sulforaphane, PEITC, and Curcumin in Cancer Prevention

  • Christina N. Ramirez
  • Wenji Li
  • Chengyue Zhang
  • Renyi Wu
  • Shan Su
  • Chao Wang
  • Linbo Gao
  • Ran Yin
  • Ah-Ng KongEmail author
Review Article Theme: Natural Products Drug Discovery in Cancer Prevention
Part of the following topical collections:
  1. Theme: Natural Products Drug Discovery in Cancer Prevention


According to the National Center of Health Statistics, cancer was the culprit of nearly 600,000 deaths in 2016 in the USA. It is by far one of the most heterogeneous diseases to treat. Treatment for metastasized cancers remains a challenge despite modern diagnostics and treatment regimens. For this reason, alternative approaches are needed. Chemoprevention using dietary phytochemicals such as triterpenoids, isothiocyanates, and curcumin in the prevention of initiation and/or progression of cancer poses a promising alternative strategy. However, significant challenges exist in the extrapolation of in vitro cell culture data to in vivo efficacy in animal models and to humans. In this review, the dose at which these phytochemicals elicit a response in vitro and in vivo of a multitude of cellular signaling pathways will be reviewed highlighting Nrf2-mediated antioxidative stress, anti-inflammation, epigenetics, cytoprotection, differentiation, and growth inhibition. The in vitro-in vivo dose response of phytochemicals can vary due, in part, to the cell line/animal model used, the assay system of the biomarker used for the readout, chemical structure of the functional analog of the phytochemical, and the source of compounds used for the treatment study. While the dose response varies across different experimental designs, the chemopreventive efficacy appears to remain and demonstrate the therapeutic potential of triterpenoids, isothiocyanates, and curcumin in cancer prevention and in health in general.


triterpenoids isothiocyanates curcumin chemoprevention phytochemical 



The authors express sincere gratitude to all of the members of Dr. Kong’s laboratory for their helpful discussions.

Funding Information

This work was supported in part by institutional funds and by R01-CA200129 from the National Cancer Institute (NCI), R01-AT009152 from the National Center for Complementary and Integrative Health (NCCIH) and R01-AT007065 from NCCIH and the Office of Dietary Supplements (ODS).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there are no conflicts of interest.


  1. 1.
    Estimated new cases and deaths from skin (nonmelanoma) cancer in the United States in 2010. National Cancer Institute (NCI); 2010; Available from:
  2. 2.
    Sporn MB. Perspective: the big C—for chemoprevention. Nature. 2011;471(7339):S10–1. Scholar
  3. 3.
    Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, et al. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res. 2008;25(9):2097–116. Scholar
  4. 4.
    Cameron EFaR. Advances in cancer research. New York: Academic Press, INC; 1980. p. 331. Google Scholar
  5. 5.
    Lee JH, Khor TO, Shu L, Su ZY, Fuentes F, Kong AN. Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression. Pharmacol Ther. 2013;137(2):153–71. Scholar
  6. 6.
    Kensler TW, Wakabayashi N. Nrf2: friend or foe for chemoprevention? Carcinogenesis. 2010;31(1):90–9. Scholar
  7. 7.
    Liby KT, Yore MM, Sporn MB. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer. 2007;7(5):357–69. Scholar
  8. 8.
    Perl A, Hanczko R, Telarico T, Oaks Z, Landas S. Oxidative stress, inflammation and carcinogenesis are controlled through the pentose phosphate pathway by transaldolase. Trends Mol Med. 2011;17(7):395–403. Scholar
  9. 9.
    Shanmugam MK, Dai X, Kumar AP, Tan BK, Sethi G, Bishayee A. Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: preclinical and clinical evidence. Cancer Lett. 2014;346(2):206–16. Scholar
  10. 10.
    Liu J. Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol. 1995;49(2):57–68. Scholar
  11. 11.
    Yang L, Shi W, Wang X, Zhou L, Cai Y, Liu H, et al. Effect of ursolic acid on proliferation of T lymphoma cell lines Hut-78 cells and its mechanism. Zhonghua Xue Ye Xue Za Zhi. 2015;36(2):153–7. Scholar
  12. 12.
    Cho J, Rho O, Junco J, Carbajal S, Siegel D, Slaga TJ, et al. Effect of combined treatment with ursolic acid and resveratrol on skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Prev Res. 2015;8(9):817–25. Scholar
  13. 13.
    Aguiriano-Moser V, Svejda B, Li ZX, Sturm S, Stuppner H, Ingolic E, et al. Ursolic acid from Trailliaedoxa gracilis induces apoptosis in medullary thyroid carcinoma cells. Mol Med Rep. 2015;12(4):5003–11. Scholar
  14. 14.
    Zhang Y, Kong C, Zeng Y, Wang L, Li Z, Wang H, et al. Ursolic acid induces PC-3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro. Mol Carcinog. 2010;49(4):374–85. Scholar
  15. 15.
    Kassi E, Papoutsi Z, Pratsinis H, Aligiannis N, Manoussakis M, Moutsatsou P. Ursolic acid, a naturally occurring triterpenoid, demonstrates anticancer activity on human prostate cancer cells. J Cancer Res Clin Oncol. 2007;133(7):493–500. Scholar
  16. 16.
    Prasad S, Yadav VR, Sung B, Gupta SC, Tyagi AK, Aggarwal BB. Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment. Oncotarget. 2016;7(11):13182–96. Scholar
  17. 17.
    Gayathri R, Priya DK, Gunassekaran GR, Sakthisekaran D. Ursolic acid attenuates oxidative stress-mediated hepatocellular carcinoma induction by diethylnitrosamine in male Wistar rats. Asian Pac J Cancer Prev. 2009;10(5):933–8.PubMedGoogle Scholar
  18. 18.
    Kowalczyk MC, Walaszek Z, Kowalczyk P, Kinjo T, Hanausek M, Slaga TJ. Differential effects of several phytochemicals and their derivatives on murine keratinocytes in vitro and in vivo: implications for skin cancer prevention. Carcinogenesis. 2009;30(6):1008–15. Scholar
  19. 19.
    Checker R, Sandur SK, Sharma D, Patwardhan RS, Jayakumar S, Kohli V, et al. Potent anti-inflammatory activity of ursolic acid, a triterpenoid antioxidant, is mediated through suppression of NF-kappaB, AP-1 and NF-AT. PLoS One. 2012;7(2):e31318. Scholar
  20. 20.
    Chun J, Lee C, Hwang SW, Im JP, Kim JS. Ursolic acid inhibits nuclear factor-kappaB signaling in intestinal epithelial cells and macrophages, and attenuates experimental colitis in mice. Life Sci. 2014;110(1):23–34. Scholar
  21. 21.
    Ramos AA, Pereira-Wilson C, Collins AR. Protective effects of ursolic acid and luteolin against oxidative DNA damage include enhancement of DNA repair in Caco-2 cells. Mutat Res. 2010;692(1–2):6–11. Scholar
  22. 22.
    Tsai SJ, Yin MC. Antioxidative and anti-inflammatory protection of oleanolic acid and ursolic acid in PC12 cells. J Food Sci. 2008;73(7):H174–8. Scholar
  23. 23.
    Wu J, Zhao S, Tang Q, Zheng F, Chen Y, Yang L, et al. Activation of SAPK/JNK mediated the inhibition and reciprocal interaction of DNA methyltransferase 1 and EZH2 by ursolic acid in human lung cancer cells. J Exp Clin Cancer Res. 2015;34(1):99. Scholar
  24. 24.
    Chen IH, Lu MC, Du YC, Yen MH, Wu CC, Chen YH, et al. Cytotoxic triterpenoids from the stems of Microtropis japonica. J Nat Prod. 2009;72(7):1231–6. Scholar
  25. 25.
    Bonaccorsi I, Altieri F, Sciamanna I, Oricchio E, Grillo C, Contartese G, et al. Endogenous reverse transcriptase as a mediator of ursolic acid’s anti-proliferative and differentiating effects in human cancer cell lines. Cancer Lett. 2008;263(1):130–9. Scholar
  26. 26.
    Zhang T, He YM, Wang JS, Shen J, Xing YY, Xi T. Ursolic acid induces HL60 monocytic differentiation and upregulates C/EBPbeta expression by ERK pathway activation. Anti-Cancer Drugs. 2011;22(2):158–65. Scholar
  27. 27.
    Zhang J, Wang W, Qian L, Zhang Q, Lai D, Qi C. Ursolic acid inhibits the proliferation of human ovarian cancer stem-like cells through epithelial-mesenchymal transition. Oncol Rep. 2015;34(5):2375–84. Scholar
  28. 28.
    Ramirez-Rodriguez AM, Gonzalez-Ortiz M, Martinez-Abundis E, Acuna Ortega N. Effect of ursolic acid on metabolic syndrome, insulin sensitivity, and inflammation. J Med Food. 2017;20(9):882–6. Scholar
  29. 29.
    Cho YH, Lee SY, Kim CM, Kim ND, Choe S, Lee CH, et al. Effect of Loquat leaf extract on muscle strength, muscle mass, and muscle function in healthy adults: a randomized, double-blinded, and placebo-controlled trial. Evid Based Complement Alternat Med. 2016;2016:4301621–9. Scholar
  30. 30.
    Tang L, Zirpoli GR, Guru K, Moysich KB, Zhang Y, Ambrosone CB, et al. Intake of cruciferous vegetables modifies bladder cancer survival. Cancer Epidemiol Biomark Prev. 2010;19(7):1806–11. Scholar
  31. 31.
    Palmer S. Diet, nutrition, and cancer. Prog Food Nutr Sci. 1985;9(3–4):283–341.PubMedGoogle Scholar
  32. 32.
    Fahey JW, Zalcmann AT, Talalay P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry. 2001;56(1):5–51. Scholar
  33. 33.
    Kliebenstein DJ, Kroymann J, Mitchell-Olds T. The glucosinolate-myrosinase system in an ecological and evolutionary context. Curr Opin Plant Biol. 2005;8(3):264–71. Scholar
  34. 34.
    Gupta P, Kim B, Kim SH, Srivastava SK. Molecular targets of isothiocyanates in cancer: recent advances. Mol Nutr Food Res. 2014;58(8):1685–707. Scholar
  35. 35.
    Keum YS, Jeong WS, Kong AN. Chemopreventive functions of isothiocyanates. Drug News Perspect. 2005;18(7):445–51. Scholar
  36. 36.
    Hayes JD, Kelleher MO, Eggleston IM. The cancer chemopreventive actions of phytochemicals derived from glucosinolates. Eur J Nutr. 2008;47(Suppl 2):73–88. Scholar
  37. 37.
    Ji Y, Kuo Y, Morris ME. Pharmacokinetics of dietary phenethyl isothiocyanate in rats. Pharm Res. 2005;22(10):1658–66. Scholar
  38. 38.
    Mi L, Wang X, Govind S, Hood BL, Veenstra TD, Conrads TP, et al. The role of protein binding in induction of apoptosis by phenethyl isothiocyanate and sulforaphane in human non-small lung cancer cells. Cancer Res. 2007;67(13):6409–16. Scholar
  39. 39.
    Hu R, Hebbar V, Kim BR, Chen C, Winnik B, Buckley B, et al. In vivo pharmacokinetics and regulation of gene expression profiles by isothiocyanate sulforaphane in the rat. J Pharmacol Exp Ther. 2004;310(1):263–71. Scholar
  40. 40.
    Hu R, Khor TO, Shen G, Jeong WS, Hebbar V, Chen C, et al. Cancer chemoprevention of intestinal polyposis in ApcMin/+ mice by sulforaphane, a natural product derived from cruciferous vegetable. Carcinogenesis. 2006;27(10):2038–46. Scholar
  41. 41.
    Yuan JM, Stepanov I, Murphy SE, Wang R, Allen S, Jensen J, et al. Clinical trial of 2-phenethyl isothiocyanate as an inhibitor of metabolic activation of a tobacco-specific lung carcinogen in cigarette smokers. Cancer Prev Res. 2016;9(5):396–405. Scholar
  42. 42.
    Cipolla BG, Mandron E, Lefort JM, Coadou Y, Della Negra E, Corbel L, et al. Effect of sulforaphane in men with biochemical recurrence after radical prostatectomy. Cancer Prev Res. 2015;8(8):712–9. Scholar
  43. 43.
    Zhang Z, Atwell LL, Farris PE, Ho E, Shannon J. Associations between cruciferous vegetable intake and selected biomarkers among women scheduled for breast biopsies. Public Health Nutr. 2016;19(7):1288–95. Scholar
  44. 44.
    Cheung KL, Kong AN. Molecular targets of dietary phenethyl isothiocyanate and sulforaphane for cancer chemoprevention. AAPS J. 2010;12(1):87–97. Scholar
  45. 45.
    Munday R, Munday CM. Induction of phase II detoxification enzymes in rats by plant-derived isothiocyanates: comparison of allyl isothiocyanate with sulforaphane and related compounds. J Agric Food Chem. 2004;52(7):1867–71. Scholar
  46. 46.
    Bacon JR, Williamson G, Garner RC, Lappin G, Langouet S, Bao Y. Sulforaphane and quercetin modulate PhIP-DNA adduct formation in human HepG2 cells and hepatocytes. Carcinogenesis. 2003;24(12):1903–11. Scholar
  47. 47.
    Dingley KH, Ubick EA, Chiarappa-Zucca ML, Nowell S, Abel S, Ebeler SE, et al. Effect of dietary constituents with chemopreventive potential on adduct formation of a low dose of the heterocyclic amines PhIP and IQ and phase II hepatic enzymes. Nutr Cancer. 2003;46(2):212–21. Scholar
  48. 48.
    Hu R, Xu C, Shen G, Jain MR, TO K, Gopalkrishnan A, et al. Identification of Nrf2-regulated genes induced by chemopreventive isothiocyanate PEITC by oligonucleotide microarray. Life Sci. 2006;79(20):1944–55. Scholar
  49. 49.
    Millington GW. Epigenetics and dermatological disease. Pharmacogenomics. 2008;9(12):1835–50. Scholar
  50. 50.
    Xu C, Yuan X, Pan Z, Shen G, Kim JH, Yu S, et al. Mechanism of action of isothiocyanates: the induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2. Mol Cancer Ther. 2006;5(8):1918–26. Scholar
  51. 51.
    Hong F, Freeman ML, Liebler DC. Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol. 2005;18(12):1917–26. Scholar
  52. 52.
    Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, et al. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci U S A. 2001;98(6):3410–5. Scholar
  53. 53.
    Khor TO, Huang MT, Prawan A, Liu Y, Hao X, Yu S, et al. Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer. Cancer Prev Res. 2008;1(3):187–91. Scholar
  54. 54.
    Xu C, Huang MT, Shen G, Yuan X, Lin W, Khor TO, et al. Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2. Cancer Res. 2006;66(16):8293–6. Scholar
  55. 55.
    Xu C, Shen G, Chen C, Gelinas C, Kong AN. Suppression of NF-kappaB and NF-kappaB-regulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells. Oncogene. 2005;24(28):4486–95. Scholar
  56. 56.
    Jeong WS, Kim IW, Hu R, Kong AN. Modulatory properties of various natural chemopreventive agents on the activation of NF-kappaB signaling pathway. Pharm Res. 2004;21(4):661–70. Scholar
  57. 57.
    Heiss E, Gerhauser C. Time-dependent modulation of thioredoxin reductase activity might contribute to sulforaphane-mediated inhibition of NF-kappaB binding to DNA. Antioxid Redox Signal. 2005;7(11–12):1601–11. Scholar
  58. 58.
    Heiss E, Herhaus C, Klimo K, Bartsch H, Gerhauser C. Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. J Biol Chem. 2001;276(34):32008–15. Scholar
  59. 59.
    Liao BC, Hsieh CW, Lin YC, Wung BS. The glutaredoxin/glutathione system modulates NF-kappaB activity by glutathionylation of p65 in cinnamaldehyde-treated endothelial cells. Toxicol Sci. 2010;116(1):151–63. Scholar
  60. 60.
    Bellezza I, Tucci A, Galli F, Grottelli S, Mierla AL, Pilolli F, et al. Inhibition of NF-kappaB nuclear translocation via HO-1 activation underlies alpha-tocopheryl succinate toxicity. J Nutr Biochem. 2012;23(12):1583–91. Scholar
  61. 61.
    Wagner AE, Will O, Sturm C, Lipinski S, Rosenstiel P, Rimbach G. DSS-induced acute colitis in C57BL/6 mice is mitigated by sulforaphane pre-treatment. J Nutr Biochem. 2013;24(12):2085–91. Scholar
  62. 62.
    Saw CL, Huang MT, Liu Y, Khor TO, Conney AH, Kong AN. Impact of Nrf2 on UVB-induced skin inflammation/photoprotection and photoprotective effect of sulforaphane. Mol Carcinog. 2011;50(6):479–86. Scholar
  63. 63.
    Wong CP, Hsu A, Buchanan A, Palomera-Sanchez Z, Beaver LM, Houseman EA, et al. Effects of sulforaphane and 3,3′-diindolylmethane on genome-wide promoter methylation in normal prostate epithelial cells and prostate cancer cells. PLoS One. 2014;9(1):e86787. Scholar
  64. 64.
    Wang LG, Chiao JW. Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (review). Int J Oncol. 2010;37(3):533–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Fuentes F, Paredes-Gonzalez X, Kong AT. Dietary glucosinolates sulforaphane, phenethyl isothiocyanate, indole-3-carbinol/3,3′-diindolylmethane: anti-oxidative stress/inflammation, Nrf2, epigenetics/epigenomics and cancer chemopreventive efficacy. Curr Pharmacol Rep. 2015;1(3):179–96. Scholar
  66. 66.
    Zhang C, Su ZY, Khor TO, Shu L, Kong AN. Sulforaphane enhances Nrf2 expression in prostate cancer TRAMP C1 cells through epigenetic regulation. Biochem Pharmacol. 2013;85(9):1398–404. Scholar
  67. 67.
    Su ZY, Zhang C, Lee JH, Shu L, Wu TY, Khor TO, et al. Requirement and epigenetics reprogramming of Nrf2 in suppression of tumor promoter TPA-induced mouse skin cell transformation by sulforaphane. Cancer Prev Res. 2014;7(3):319–29. Scholar
  68. 68.
    Ho E, Clarke JD, Dashwood RH. Dietary sulforaphane, a histone deacetylase inhibitor for cancer prevention. J Nutr. 2009;139(12):2393–6. Scholar
  69. 69.
    Myzak MC, Tong P, Dashwood WM, Dashwood RH, Ho E. Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects. Exp Biol Med (Maywood). 2007;232(2):227–34.Google Scholar
  70. 70.
    Myzak MC, Hardin K, Wang R, Dashwood RH, Ho E. Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells. Carcinogenesis. 2006;27(4):811–9. Scholar
  71. 71.
    Wang LG, Liu XM, Fang Y, Dai W, Chiao FB, Puccio GM, et al. De-repression of the p21 promoter in prostate cancer cells by an isothiocyanate via inhibition of HDACs and c-Myc. Int J Oncol. 2008;33(2):375–80.PubMedGoogle Scholar
  72. 72.
    Liu K, Cang S, Ma Y, Chiao JW. Synergistic effect of paclitaxel and epigenetic agent phenethyl isothiocyanate on growth inhibition, cell cycle arrest and apoptosis in breast cancer cells. Cancer Cell Int. 2013;13(1):10. Scholar
  73. 73.
    Cang S, Ma Y, Chiao JW, Liu D. Phenethyl isothiocyanate and paclitaxel synergistically enhanced apoptosis and alpha-tubulin hyperacetylation in breast cancer cells. Exp Hematol Oncol. 2014;3(1):5. Scholar
  74. 74.
    Zhang C, Shu L, Kim H, Khor TO, Wu R, Li W, et al. Phenethyl isothiocyanate (PEITC) suppresses prostate cancer cell invasion epigenetically through regulating microRNA-194. Mol Nutr Food Res. 2016;60(6):1427–36. Scholar
  75. 75.
    Zhu H, Jia Z, Strobl JS, Ehrich M, Misra HP, Li Y. Potent induction of total cellular and mitochondrial antioxidants and phase 2 enzymes by cruciferous sulforaphane in rat aortic smooth muscle cells: cytoprotection against oxidative and electrophilic stress. Cardiovasc Toxicol. 2008;8(3):115–25. Scholar
  76. 76.
    Huang CS, Lin AH, Liu CT, Tsai CW, Chang IS, Chen HW, et al. Isothiocyanates protect against oxidized LDL-induced endothelial dysfunction by upregulating Nrf2-dependent antioxidation and suppressing NFkappaB activation. Mol Nutr Food Res. 2013;57(11):1918–30. Scholar
  77. 77.
    Hofmann T, Kuhnert A, Schubert A, Gill C, Rowland IR, Pool-Zobel BL, et al. Modulation of detoxification enzymes by watercress: in vitro and in vivo investigations in human peripheral blood cells. Eur J Nutr. 2009;48(8):483–91. Scholar
  78. 78.
    Ullah MF. Sulforaphane (SFN): an isothiocyanate in a cancer chemoprevention paradigm. Medicines. 2015;2(3):141–56. Scholar
  79. 79.
    Li Y, Zhang T, Korkaya H, Liu S, Lee HF, Newman B, et al. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res. 2010;16(9):2580–90. Scholar
  80. 80.
    Fimognari C, Lenzi M, Cantelli-Forti G, Hrelia P. Induction of differentiation in human promyelocytic cells by the isothiocyanate sulforaphane. In Vivo. 2008;22(3):317–20.PubMedGoogle Scholar
  81. 81.
    Asselin-Labat ML, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC, et al. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol. 2007;9(2):201–9. Scholar
  82. 82.
    Kouros-Mehr H, Bechis SK, Slorach EM, Littlepage LE, Egeblad M, Ewald AJ, et al. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell. 2008;13(2):141–52. Scholar
  83. 83.
    Singh SV, Singh K. Cancer chemoprevention with dietary isothiocyanates mature for clinical translational research. Carcinogenesis. 2012;33(10):1833–42. Scholar
  84. 84.
    McCune K, Mehta R, Thorat MA, Badve S, Nakshatri H. Loss of ERalpha and FOXA1 expression in a progression model of luminal type breast cancer: insights from PyMT transgenic mouse model. Oncol Rep. 2010;24(5):1233–9.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Dvorankova B, Smetana K Jr, Chovanec M, Lacina L, Stork J, Plzakova Z, et al. Transient expression of keratin 19 is induced in originally negative interfollicular epidermal cells by adhesion of suspended cells. Int J Mol Med. 2005;16(4):525–31.PubMedGoogle Scholar
  86. 86.
    Gamet-Payrastre L. Signaling pathways and intracellular targets of sulforaphane mediating cell cycle arrest and apoptosis. Curr Cancer Drug Targets. 2006;6(2):135–45. Scholar
  87. 87.
    le Huong D, Shin JA, Choi ES, Cho NP, Kim HM, Leem DH, et al. Beta-phenethyl isothiocyanate induces death receptor 5 to induce apoptosis in human oral cancer cells via p38. Oral Dis. 2012;18(5):513–9. Scholar
  88. 88.
    Huongle D, Shim JH, Choi KH, Shin JA, Choi ES, Kim HS, et al. Effect of beta-phenylethyl isothiocyanate from cruciferous vegetables on growth inhibition and apoptosis of cervical cancer cells through the induction of death receptors 4 and 5. J Agric Food Chem. 2011;59(15):8124–31. Scholar
  89. 89.
    Gupta P, Adkins C, Lockman P, Srivastava SK. Metastasis of breast tumor cells to brain is suppressed by phenethyl isothiocyanate in a novel metastasis model. PLoS One. 2013;8(6):e67278. Scholar
  90. 90.
    Chen PY, Lin KC, Lin JP, Tang NY, Yang JS, Lu KW, et al. Phenethyl isothiocyanate (PEITC) inhibits the growth of human oral squamous carcinoma HSC-3 cells through G(0)/G(1) phase arrest and mitochondria-mediated apoptotic cell death. Evid Based Complement Alternat Med. 2012;2012:718320–12. Scholar
  91. 91.
    Tang NY, Huang YT, Yu CS, Ko YC, Wu SH, Ji BC, et al. Phenethyl isothiocyanate (PEITC) promotes G2/M phase arrest via p53 expression and induces apoptosis through caspase- and mitochondria-dependent signaling pathways in human prostate cancer DU 145 cells. Anticancer Res. 2011;31(5):1691–702.PubMedGoogle Scholar
  92. 92.
    Jakubikova J, Cervi D, Ooi M, Kim K, Nahar S, Klippel S, et al. Anti-tumor activity and signaling events triggered by the isothiocyanates, sulforaphane and phenethyl isothiocyanate, in multiple myeloma. Haematologica. 2011;96(8):1170–9. Scholar
  93. 93.
    Dai MY, Wang Y, Chen C, Li F, Xiao BK, Chen SM, et al. Phenethyl isothiocyanate induces apoptosis and inhibits cell proliferation and invasion in Hep-2 laryngeal cancer cells. Oncol Rep. 2016;35(5):2657–64. Scholar
  94. 94.
    Yan H, Zhu Y, Liu B, Wu H, Li Y, Wu X, et al. Mitogen-activated protein kinase mediates the apoptosis of highly metastatic human non-small cell lung cancer cells induced by isothiocyanates. Br J Nutr. 2011;106(12):1779–91. Scholar
  95. 95.
    Wu X, Zhu Y, Yan H, Liu B, Li Y, Zhou Q, et al. Isothiocyanates induce oxidative stress and suppress the metastasis potential of human non-small cell lung cancer cells. BMC Cancer. 2010;10(1):269. Scholar
  96. 96.
    Li SH, Fu J, Watkins DN, Srivastava RK, Shankar S. Sulforaphane regulates self-renewal of pancreatic cancer stem cells through the modulation of sonic hedgehog-GLI pathway. Mol Cell Biochem. 2013;373(1–2):217–27. Scholar
  97. 97.
    Singh SV, Srivastava SK, Choi S, Lew KL, Antosiewicz J, Xiao D, et al. Sulforaphane-induced cell death in human prostate cancer cells is initiated by reactive oxygen species. J Biol Chem. 2005;280(20):19911–24. Scholar
  98. 98.
    Shan Y, Sun C, Zhao X, Wu K, Cassidy A, Bao Y. Effect of sulforaphane on cell growth, G(0)/G(1) phase cell progression and apoptosis in human bladder cancer T24 cells. Int J Oncol. 2006;29(4):883–8.PubMedGoogle Scholar
  99. 99.
    Gamet-Payrastre L, Li P, Lumeau S, Cassar G, Dupont MA, Chevolleau S, et al. Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells. Cancer Res. 2000;60(5):1426–33.PubMedGoogle Scholar
  100. 100.
    Suppipat K, Park CS, Shen Y, Zhu X, Lacorazza HD. Sulforaphane induces cell cycle arrest and apoptosis in acute lymphoblastic leukemia cells. PLoS One. 2012;7(12):e51251. Scholar
  101. 101.
    Zuryn A, Litwiniec A, Safiejko-Mroczka B, Klimaszewska-Wisniewska A, Gagat M, Krajewski A, et al. The effect of sulforaphane on the cell cycle, apoptosis and expression of cyclin D1 and p21 in the A549 non-small cell lung cancer cell line. Int J Oncol. 2016;
  102. 102.
    Wang M, Chen S, Wang S, Sun D, Chen J, Li Y, et al. Effects of phytochemicals sulforaphane on uridine diphosphate-glucuronosyltransferase expression as well as cell-cycle arrest and apoptosis in human colon cancer Caco-2 cells. Chin J Physiol. 2012;55(2):134–44. Scholar
  103. 103.
    Chen MJ, Tang WY, Hsu CW, Tsai YT, Wu JF, Lin CW, et al. Apoptosis induction in primary human colorectal cancer cell lines and retarded tumor growth in SCID mice by sulforaphane. Evid Based Complement Alternat Med. 2012;2012:415231–13. Scholar
  104. 104.
    Kanematsu S, Uehara N, Miki H, Yoshizawa K, Kawanaka A, Yuri T, et al. Autophagy inhibition enhances sulforaphane-induced apoptosis in human breast cancer cells. Anticancer Res. 2010;30(9):3381–90.PubMedGoogle Scholar
  105. 105.
    Kim BR, Hu R, Keum YS, Hebbar V, Shen G, Nair SS, et al. Effects of glutathione on antioxidant response element-mediated gene expression and apoptosis elicited by sulforaphane. Cancer Res. 2003;63(21):7520–5.PubMedGoogle Scholar
  106. 106.
    Yu R, Tan TH, Kong AN. Butylated hydroxyanisole and its metabolite tert-butylhydroquinone differentially regulate mitogen-activated protein kinases. The role of oxidative stress in the activation of mitogen-activated protein kinases by phenolic antioxidants. J Biol Chem. 1997;272(46):28962–70. Scholar
  107. 107.
    Yu R, Lei W, Mandlekar S, Weber MJ, Der CJ, Wu J, et al. Role of a mitogen-activated protein kinase pathway in the induction of phase II detoxifying enzymes by chemicals. J Biol Chem. 1999;274(39):27545–52. Scholar
  108. 108.
    Kong AN, Yu R, Lei W, Mandlekar S, Tan TH, Ucker DS. Differential activation of MAPK and ICE/Ced-3 protease in chemical-induced apoptosis. The role of oxidative stress in the regulation of mitogen-activated protein kinases (MAPKs) leading to gene expression and survival or activation of caspases leading to apoptosis. Restor Neurol Neurosci. 1998;12(2–3):63–70.PubMedGoogle Scholar
  109. 109.
    Manach C, Scalbert A, Morand C, Remesy C, Jimenez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004;79(5):727–47.PubMedCrossRefGoogle Scholar
  110. 110.
    Neveu V, Perez-Jimenez J, Vos F, Crespy V, du Chaffaut L, Mennen L, et al. Phenol-explorer: an online comprehensive database on polyphenol contents in foods. Database. 2010;2010(0):bap024. Scholar
  111. 111.
    Zhou Y, Zheng J, Li Y, Xu DP, Li S, Chen YM, et al. Natural polyphenols for prevention and treatment of cancer. Nutrients. 2016;8(8)515.
  112. 112.
    Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001;21(4B):2895–900.PubMedGoogle Scholar
  113. 113.
    Heger M. Drug screening: don’t discount all curcumin trial data. Nature. 2017;543(7643):40. Scholar
  114. 114.
    Panahi Y, Saadat A, Beiraghdar F, Sahebkar A. Adjuvant therapy with bioavailability-boosted curcuminoids suppresses systemic inflammation and improves quality of life in patients with solid tumors: a randomized double-blind placebo-controlled trial. Phytother Res. 2014;28(10):1461–7. Scholar
  115. 115.
    Hejazi J, Rastmanesh R, Taleban FA, Molana SH, Hejazi E, Ehtejab G, et al. Effect of curcumin supplementation during radiotherapy on oxidative status of patients with prostate cancer: a double blinded, randomized, Placebo-Controlled Study. Nutr Cancer. 2016;68(1):77–85. Scholar
  116. 116.
    Cruz-Correa M, Shoskes DA, Sanchez P, Zhao R, Hylind LM, Wexner SD, et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2006;4(8):1035–8. Scholar
  117. 117.
    Carroll RE, Benya RV, Turgeon DK, Vareed S, Neuman M, Rodriguez L, et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res. 2011;4(3):354–64. Scholar
  118. 118.
    Scapagnini G, Colombrita C, Amadio M, D'Agata V, Arcelli E, Sapienza M, et al. Curcumin activates defensive genes and protects neurons against oxidative stress. Antioxid Redox Signal. 2006;8(3–4):395–403. Scholar
  119. 119.
    Shishodia S, Chaturvedi MM, Aggarwal BB. Role of curcumin in cancer therapy. Curr Probl Cancer. 2007;31(4):243–305. Scholar
  120. 120.
    Woo JH, Kim YH, Choi YJ, Kim DG, Lee KS, Bae JH, et al. Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt. Carcinogenesis. 2003;24(7):1199–208. Scholar
  121. 121.
    Rajasekaran SA. Therapeutic potential of curcumin in gastrointestinal diseases. World J Gastrointest Pathophysiol. 2011;2(1):1–14. Scholar
  122. 122.
    Basnet P, Skalko-Basnet N. Curcumin: an anti-inflammatory molecule from a curry spice on the path to cancer treatment. Molecules. 2011;16(6):4567–98. Scholar
  123. 123.
    Strimpakos AS, Sharma RA. Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxid Redox Signal. 2008;10(3):511–45. Scholar
  124. 124.
    Brinkmann J, Stolpmann K, Trappe S, Otter T, Genkinger D, Bock U, et al. Metabolically competent human skin models: activation and genotoxicity of benzo[a]pyrene. Toxicol Sci. 2013;131(2):351–9. Scholar
  125. 125.
    Jancinova V, Perecko T, Nosal R, Mihalova D, Bauerova K, Drabikova K. Pharmacological regulation of neutrophil activity and apoptosis: contribution to new strategy for modulation of inflammatory processes. Interdiscip Toxicol. 2011;4(1):11–4. Scholar
  126. 126.
    Zhong F, Chen H, Han L, Jin Y, Wang W. Curcumin attenuates lipopolysaccharide-induced renal inflammation. Biol Pharm Bull. 2011;34(2):226–32. Scholar
  127. 127. SCF. nonmelanoma skin cancer incidence increases dramatically. Sun & Skin News Summer2010.
  128. 128.
    Hao F, Kang J, Cao Y, Fan S, Yang H, An Y, et al. Curcumin attenuates palmitate-induced apoptosis in MIN6 pancreatic β-cells through PI3K/Akt/FoxO1 and mitochondrial survival pathways. Apoptosis. 2015;20(11):1420–32. Scholar
  129. 129.
    Zhang X, Liang D, Guo L, Liang W, Jiang Y, Li H, et al. Curcumin protects renal tubular epithelial cells from high glucose-induced epithelial-to-mesenchymal transition through Nrf2-mediated upregulation of heme oxygenase-1. Mol Med Rep. 2015;12(1):1347–55. Scholar
  130. 130.
    Alinejad B, Ghorbani A, Sadeghnia HR. Effects of combinations of curcumin, linalool, rutin, safranal, and thymoquinone on glucose/serum deprivation-induced cell death. Avicenna J Phytomed. 2013;3(4):321–8.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Nazari QA, Kume T, Izuo N, Takada-Takatori Y, Imaizumi A, Hashimoto T, et al. Neuroprotective effects of curcumin and highly bioavailable curcumin on oxidative stress induced by sodium nitroprusside in rat striatal cell culture. Biol Pharm Bull. 2013;36(8):1356–62. Scholar
  132. 132.
    Sakurai R, Villarreal P, Husain S, Liu J, Sakurai T, Tou E, et al. Curcumin protects the developing lung against long-term hyperoxic injury. Am J Physiol Lung Cell Mol Physiol. 2013;305(4):L301–11. Scholar
  133. 133.
    Chen F, Wang H, Xiang X, Yuan J, Chu W, Xue X, et al. Curcumin increased the differentiation rate of neurons in neural stem cells via wnt signaling in vitro study. J Surg Res. 2014;192(2):298–304. Scholar
  134. 134.
    Mujoo K, Nikonoff LE, Sharin VG, Bryan NS, Kots AY, Murad F. Curcumin induces differentiation of embryonic stem cells through possible modulation of nitric oxide-cyclic GMP pathway. Protein Cell. 2012;3(7):535–44. Scholar
  135. 135.
    Tu SP, Jin H, Shi JD, Zhu LM, Suo Y, Lu G, et al. Curcumin induces the differentiation of myeloid-derived suppressor cells and inhibits their interaction with cancer cells and related tumor growth. Cancer Prev Res. 2012;5(2):205–15. Scholar
  136. 136.
    Kim CY, Le TT, Chen C, Cheng JX, Kim KH. Curcumin inhibits adipocyte differentiation through modulation of mitotic clonal expansion. J Nutr Biochem. 2011;22(10):910–20. Scholar
  137. 137.
    Liu H, Liu A, Shi C, Li B. Curcumin suppresses transforming growth factor-beta1-induced cardiac fibroblast differentiation via inhibition of Smad-2 and p38 MAPK signaling pathways. Exp Ther Med. 2016;11(3):998–1004. Scholar
  138. 138.
    Ma J, Ma SY, Ding CH. Curcumin reduces cardiac fibrosis by inhibiting myofibroblast differentiation and decreasing transforming growth factor beta1 and matrix metalloproteinase 9 / tissue inhibitor of metalloproteinase 1. Chin J Integr Med. 2016.
  139. 139. HC. Metastasis of squamous cell carcinoma.
  140. 140.
    Guo Y, Shu L, Zhang C, Su ZY, Kong AN. Curcumin inhibits anchorage-independent growth of HT29 human colon cancer cells by targeting epigenetic restoration of the tumor suppressor gene DLEC1. Biochem Pharmacol. 2015;94(2):69–78. Scholar
  141. 141.
    Khar A, Ali AM, Pardhasaradhi BV, Varalakshmi CH, Anjum R, Kumari AL. Induction of stress response renders human tumor cell lines resistant to curcumin-mediated apoptosis: role of reactive oxygen intermediates. Cell Stress Chaperones. 2001;6(4):368–76.<0368:IOSRRH>2.0.CO;2.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Chan WH, Wu HY, Chang WH. Dosage effects of curcumin on cell death types in a human osteoblast cell line. Food Chem Toxicol. 2006;44(8):1362–71. Scholar
  143. 143.
    Chen J, Wanming D, Zhang D, Liu Q, Kang J. Water-soluble antioxidants improve the antioxidant and anticancer activity of low concentrations of curcumin in human leukemia cells. Pharmazie. 2005;60(1):57–61.PubMedGoogle Scholar
  144. 144.
    Banerjee A, Kunwar A, Mishra B, Priyadarsini KI. Concentration dependent antioxidant/pro-oxidant activity of curcumin studies from AAPH induced hemolysis of RBCs. Chem Biol Interact. 2008;174(2):134–9. Scholar
  145. 145.
    Ali RE, Rattan SI. Curcumin's biphasic hormetic response on proteasome activity and heat-shock protein synthesis in human keratinocytes. Ann N Y Acad Sci. 2006;1067(1):394–9. Scholar
  146. 146.
    Calabrese EJ, Baldwin LA. Hormesis: the dose-response revolution. Annu Rev Pharmacol Toxicol. 2003;43(1):175–97. Scholar
  147. 147.
    Calabrese EJ. Hormesis: why it is important to toxicology and toxicologists. Environ Toxicol Chem. 2008;27(7):1451–74. Scholar
  148. 148.
    Borriello A, Bencivenga D, Caldarelli I, Tramontano A, Borgia A, Pirozzi AV, et al. Resveratrol and cancer treatment: is hormesis a yet unsolved matter? Curr Pharm Des. 2013;19(30):5384–93. Scholar
  149. 149.
    Bao J, Huang B, Zou L, Chen S, Zhang C, Zhang Y, et al. Hormetic effect of berberine attenuates the anticancer activity of chemotherapeutic agents. PLoS One. 2015;10(9):e0139298. Scholar
  150. 150.
    Haddi K, Oliveira EE, Faroni LR, Guedes DC, Miranda NN. Sublethal exposure to clove and cinnamon essential oils induces hormetic-like responses and disturbs behavioral and respiratory responses in Sitophilus Zeamais (Coleoptera: Curculionidae). J Econ Entomol. 2015;108(6):2815–22. Scholar
  151. 151.
    Sun B, Ross SM, Trask OJ, Carmichael PL, Dent M, White A, et al. Assessing dose-dependent differences in DNA-damage, p53 response and genotoxicity for quercetin and curcumin. Toxicol In Vitro. 2013;27(6):1877–87. Scholar
  152. 152.
    Khor TO, Huang Y, Wu TY, Shu L, Lee J, Kong AN. Pharmacodynamics of curcumin as DNA hypomethylation agent in restoring the expression of Nrf2 via promoter CpGs demethylation. Biochem Pharmacol. 2011;82(9):1073–8. Scholar
  153. 153.
    Hager B, Bickenbach JR, Fleckman P. Long-term culture of murine epidermal keratinocytes. J Invest Dermatol. 1999;112(6):971–6. Scholar
  154. 154.
    Shu L, TO K, Lee JH, Boyanapalli SS, Huang Y, Wu TY, et al. Epigenetic CpG demethylation of the promoter and reactivation of the expression of Neurog1 by curcumin in prostate LNCaP cells. AAPS J. 2011;13(4):606–14. Scholar
  155. 155.
    Mirza S, Sharma G, Parshad R, Gupta SD, Pandya P, Ralhan R. Expression of DNA methyltransferases in breast cancer patients and to analyze the effect of natural compounds on DNA methyltransferases and associated proteins. J Breast Cancer. 2013;16(1):23–31. Scholar
  156. 156.
    Li W, Pung D, Su ZY, Guo Y, Zhang C, Yang AY, et al. Epigenetics reactivation of Nrf2 in prostate TRAMP C1 cells by curcumin analogue FN1. Chem Res Toxicol. 2016;29(4):694–703. Scholar
  157. 157.
    Chiu S, Terpstra KJ, Bureau Y, Hou J, Raheb H, Cernvosky Z, et al. Liposomal-formulated curcumin [Lipocurc] targeting HDAC (histone deacetylase) prevents apoptosis and improves motor deficits in Park 7 (DJ-1)-knockout rat model of Parkinson's disease: implications for epigenetics-based nanotechnology-driven drug platform. J Complement Integr Med. 2013;10(1).
  158. 158.
    Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004;101(9):2999–3004. Scholar
  159. 159.
    Saini S, Arora S, Majid S, Shahryari V, Chen Y, Deng G, et al. Curcumin modulates microRNA-203-mediated regulation of the Src-Akt axis in bladder cancer. Cancer Prev Res. 2011;4(10):1698–709. Scholar
  160. 160.
    Su ZY, Shu L, Khor TO, Lee JH, Fuentes F, Kong AN. A perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, nrf2, and epigenomics. Top Curr Chem. 2013;329:133–62. Scholar
  161. 161.
    Chen C, Kong AN. Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects. Trends Pharmacol Sci. 2005;26(6):318–26. Scholar
  162. 162.
    Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998;78(2):547–81.PubMedCrossRefGoogle Scholar
  163. 163.
    Halliwell B, Gutteridge J. Free radicals in biology and medicine. Oxford: Oxford University Press; 1999.Google Scholar
  164. 164.
    Lander HM. An essential role for free radicals and derived species in signal transduction. FASEB J. 1997;11(2):118–24.PubMedCrossRefGoogle Scholar
  165. 165.
    Yu BP. Cellular defenses against damage from reactive oxygen species. Physiol Rev. 1994;74(1):139–62.PubMedCrossRefGoogle Scholar
  166. 166.
    Emerit J, Edeas M, Bricaire F. Neurodegenerative diseases and oxidative stress. Biomed Pharmacother. 2004;58(1):39–46. Scholar
  167. 167.
    Cataldi A. Cell responses to oxidative stressors. Curr Pharm Des. 2010;16(12):1387–95. Scholar
  168. 168.
    Molinolo AA, Amornphimoltham P, Squarize CH, Castilho RM, Patel V, Gutkind JS. Dysregulated molecular networks in head and neck carcinogenesis. Oral Oncol. 2009;45(4–5):324–34. Scholar
  169. 169.
    Wolffe AP, Matzke MA. Epigenetics: regulation through repression. Science. 1999;286(5439):481–6. Scholar
  170. 170.
    Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358(11):1148–59. Scholar
  171. 171.
    Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet. 2005;37(4):391–400. Scholar
  172. 172.
    Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3(6):415–28. Scholar
  173. 173.
    Nakayama M, Gonzalgo ML, Yegnasubramanian S, Lin X, De Marzo AM, Nelson WG. GSTP1 CpG island hypermethylation as a molecular biomarker for prostate cancer. J Cell Biochem. 2004;91(3):540–52. Scholar
  174. 174.
    Nelson WG, Yegnasubramanian S, Agoston AT, Bastian PJ, Lee BH, Nakayama M, et al. Abnormal DNA methylation, epigenetics, and prostate cancer. Front Biosci. 2007;12(8-12):4254–66. Scholar
  175. 175.
    Nelson WG, De Marzo AM, Yegnasubramanian S. Epigenetic alterations in human prostate cancers. Endocrinology. 2009;150(9):3991–4002. Scholar
  176. 176.
    Jeronimo C, Henrique R. Epigenetic biomarkers in urological tumors: a systematic review. Cancer Lett. 2014;342(2):264–74. Scholar
  177. 177.
    Sandoval J, Esteller M. Cancer epigenomics: beyond genomics. Curr Opin Genet Dev. 2012;22(1):50–5. Scholar
  178. 178.
    Lee WH, Morton RA, Epstein JI, Brooks JD, Campbell PA, Bova GS, et al. Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc Natl Acad Sci U S A. 1994;91(24):11733–7. Scholar
  179. 179.
    Lee WH, Isaacs WB, Bova GS, Nelson WG. CG island methylation changes near the GSTP1 gene in prostatic carcinoma cells detected using the polymerase chain reaction: a new prostate cancer biomarker. Cancer Epidemiol Biomark Prev. 1997;6(6):443–50.Google Scholar
  180. 180.
    Santourlidis S, Florl A, Ackermann R, Wirtz HC, Schulz WA. High frequency of alterations in DNA methylation in adenocarcinoma of the prostate. Prostate. 1999;39(3):166–74.<166::AID-PROS4>3.0.CO;2-J.PubMedCrossRefGoogle Scholar
  181. 181.
    van Doorn R, Gruis NA, Willemze R, van der Velden PA, Tensen CP. Aberrant DNA methylation in cutaneous malignancies. Semin Oncol. 2005;32(5):479–87. Scholar
  182. 182.
    Bachman AN, Curtin GM, Doolittle DJ, Goodman JI. Altered methylation in gene-specific and GC-rich regions of DNA is progressive and nonrandom during promotion of skin tumorigenesis. Toxicol Sci. 2006;91(2):406–18. Scholar
  183. 183.
    Schinke C, Mo Y, Yu Y, Amiri K, Sosman J, Greally J, et al. Aberrant DNA methylation in malignant melanoma. Melanoma Res. 2010;20(4):253–65. Scholar
  184. 184.
    Helin K, Dhanak D. Chromatin proteins and modifications as drug targets. Nature. 2013;502(7472):480–8. Scholar
  185. 185.
    Davis CD, Uthus EO. DNA methylation, cancer susceptibility, and nutrient interactions. Exp Biol Med (Maywood). 2004;229(10):988–95. Scholar
  186. 186.
    Fang M, Chen D, Yang CS. Dietary polyphenols may affect DNA methylation. J Nutr. 2007;137(1 Suppl):223S–8S.PubMedCrossRefGoogle Scholar
  187. 187.
    Yang CS, Fang M, Lambert JD, Yan P, Huang TH. Reversal of hypermethylation and reactivation of genes by dietary polyphenolic compounds. Nutr Rev. 2008;66(Suppl 1):S18–20. Scholar
  188. 188.
    Rajasekhar VK. Cancer stem cells. Hoboken: John Wiley & Sons; 2014. Scholar
  189. 189.
    Taipale J, Beachy PA. The hedgehog and Wnt signalling pathways in cancer. Nature. 2001;411(6835):349–54. Scholar
  190. 190.
    Katoh M. Networking of WNT, FGF, notch, BMP, and hedgehog signaling pathways during carcinogenesis. Stem Cell Rev. 2007;3(1):30–8. Scholar
  191. 191.
    Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J, et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol. 2009;7(6):e1000121. Scholar
  192. 192.
    Liu S, Dontu G, Wicha MS. Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res. 2005;7(3):86–95. Scholar
  193. 193.
    Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730–7. Scholar
  194. 194.
    Dawood S, Austin L, Cristofanilli M. Cancer stem cells: implications for cancer therapy. Oncology (Williston Park). 2014;28(12):1101–7. 10 Google Scholar
  195. 195.
    Katoh M. Canonical and non-canonical WNT signaling in cancer stem cells and their niches: cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (review). Int J Oncol. 2017;51(5):1357–69. Scholar
  196. 196.
    Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov. 2009;8(10):806–23. Scholar
  197. 197.
    Kawasaki BT, Hurt EM, Mistree T, Farrar WL. Targeting cancer stem cells with phytochemicals. Mol Interv. 2008;8(4):174–84. Scholar
  198. 198.
    Ichim G, Tait SW. A fate worse than death: apoptosis as an oncogenic process. Nat Rev Cancer. 2016;16(8):539–48. Scholar
  199. 199.
    Chun KS, Kundu J, Kundu JK, Surh YJ. Targeting Nrf2-Keap1 signaling for chemoprevention of skin carcinogenesis with bioactive phytochemicals. Toxicol Lett. 2014;229(1):73–84. Scholar
  200. 200.
    Zhang Y, Kong C, Zeng Y, Wang L, Li Z, Wang H, et al. Ursolic acid induces PC-3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro. Mol Carcinog. 49(4):374–85.
  201. 201.
    Wang LG, Beklemisheva A, Liu XM, Ferrari AC, Feng J, Chiao JW. Dual action on promoter demethylation and chromatin by an isothiocyanate restored GSTP1 silenced in prostate cancer. Mol Carcinog. 2007;46(1):24–31. Scholar
  202. 202.
    Kim H, Ramirez CN, Su ZY, Kong AN. Epigenetic modifications of triterpenoid ursolic acid in activating Nrf2 and blocking cellular transformation of mouse epidermal cells. J Nutr Biochem. 2016;33:54–62. Scholar
  203. 203.
    Su ZY, Zhang C, Lee JH, Shu L, Wu TY, Khor TO, et al. Requirement and epigenetics reprogramming of Nrf2 in suppression of tumor promoter TPA-induced mouse skin cell transformation by sulforaphane. Cancer Prev Res. 2014.

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Christina N. Ramirez
    • 1
    • 2
  • Wenji Li
    • 1
    • 3
  • Chengyue Zhang
    • 1
    • 3
    • 4
  • Renyi Wu
    • 1
    • 3
  • Shan Su
    • 1
    • 3
  • Chao Wang
    • 1
    • 3
  • Linbo Gao
    • 1
    • 3
  • Ran Yin
    • 1
    • 3
  • Ah-Ng Kong
    • 1
    • 3
    • 4
    • 5
    Email author
  1. 1.Center for Phytochemicals Epigenome Studies, Ernest Mario School of PharmacyRutgers, The State University of New JerseyPiscatawayUSA
  2. 2.Cellular and Molecular Pharmacology ProgramRutgers Robert Wood Johnson Medical SchoolPiscatawayUSA
  3. 3.Department of Pharmaceutics, Ernest Mario School of PharmacyRutgers, The State University of New JerseyPiscatawayUSA
  4. 4.Graduate Program in Pharmaceutical Sciences, Department of Pharmaceutics, Ernest Mario School of PharmacyRutgers, The State University of New JerseyPiscatawayUSA
  5. 5.Ernest Mario School of Pharmacy, Room 228Rutgers, The State University of New JerseyPiscatawayUSA

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