Chung S. Yang Professor Rutgers University Department of Chemical Biology Ernest Mario School of Pharmacy 164 Frelinghuysen Road Piscataway. N.J. 08854-0789 (732) 445-3400. Ext 248 FAX -0687 csyang@rci.rutgers.edu

Molecular mechanisms of carcinogenesis and its prevention

The research program is focused on studying the molecular mechanisms of carcinogenesis and designing strategies and agents for the prevention of cancer. Specific projects involve: 1) characterizing the molecular alterations at different stages of esophageal cancer development in animal models and human tissues; 2) studying inflammation. carcinogenesis. and cancer prevention in animal models for esophageal adenocarcinoma and ulcerative colitis-associated colon carcinogenesis; 3) studying the cancer preventive activity of tea. curcumin. genistein. and other dietary constituents. and combinations thereof with synthetic compounds in animal models for lung. oral. esophageal. intestinal. and colon cancers. The molecular mechanisms of action as well as the metabolism and bioavailability of these compounds are being studied in cell lines. animal models. and humans.

Selected Publications

Xiao H, Yang CS. (2008) Combination regimen with statins and NSAIDs: a promising strategy for cancer chemoprevention. Int J Cancer. 123(5):983-90.

Zhang X, Zhang H, Tighiouart M, Lee JE, Shin HJ, Khuri FR, Yang CS, Chen ZG, Shin DM. (2008) Synergistic inhibition of head and neck tumor growth by green tea -epigallocatechin-3-gallate and EGFR tyrosine kinase inhibitor. Int J Cancer. 123(5):1005-14.

Yang CS, Ju J, Lu G, Xiao H, Hao X, Sang S, Lambert JD. (2008) Cancer prevention by tea and tea polyphenols. Asia Pac J Clin Nutr. 17 Suppl 1:245-8.

Barve A, Khor TO, Hao X, Keum YS, Yang CS, Reddy B, Kong AN. (2008) Murine Prostate Cancer Inhibition by Dietary Phytochemicals-Curcumin and Phenyethylisothiocyanate. Pharm Res. Apr 25. [Epub ahead of print]

Sang S, Lee MJ, Yang I, Buckley B, Yang CS. (2008) Human urinary metabolite profile of tea polyphenols analyzed by liquid chromatography/electrospray ionization tandem mass spectrometry with data-dependent acquisition. Rapid Commun Mass Spectrom. 22(10):1567-78.

Lambert JD, Sang S, Yang CS. (2008) N-Acetylcysteine enhances the lung cancer inhibitory effect of epigallocatechin-3-gallate and forms a new adduct. Free Radic Biol Med. 44(6):1069-74.

Chen X, Qin R, Liu B, Ma Y, Su Y, Yang CS, Glickman JN, Odze RD, Shaheen NJ. (2008) Multilayered epithelium in a rat model and human Barrett's esophagus: similar expression patterns of transcription factors and differentiation markers. BMC Gastroenterol. 8:1.

Xiao H, Zhang Q, Lin Y, Reddy BS, Yang CS. (2008) Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells. Int J Cancer. 122(9):2115-24.

He Z, Tang F, Ermakova S, Li M, Zhao Q, Cho YY, Ma WY, Choi HS, Bode AM, Yang CS, Dong Z.
(2008) Fyn is a novel target of (-)-epigallocatechin gallate in the inhibition of JB6 Cl41 cell transformation. Mol Carcinog. 47(3):172-83.

Sang S, Shao X, Bai N, Lo CY, Yang CS, Ho CT. (2007) Tea polyphenol (-)-epigallocatechin-3-gallate: a new trapping agent of reactive dicarbonyl species. Chem Res Toxicol. 20(12):1862-70.

Lambert JD, Sang S, Yang CS. (2007) Biotransformation of green tea polyphenols and the biological activities of those metabolites. Mol Pharm. 4(6):819-25.

Sun Z, Sood S, Li N, Yang P, Newman RA, Yang CS, Chen X. (2008) Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamster cheek pouch by topical application of a dual inhibitor of epidermal growth factor receptor (EGFR) and ErbB2 tyrosine kinases. Oral Oncol. 44(7):652-7.

Suh N, Paul S, Lee HJ, Ji Y, Lee MJ, Yang CS, Reddy BS, Newmark HL. (2007) Mixed tocopherols inhibit N-methyl-N-nitrosourea-induced mammary tumor growth in rats. Nutr Cancer. 59(1):76-81.

Hao X, Sun Y, Yang CS, Bose M, Lambert JD, Ju J, Lu G, Lee MJ, Park S, Husain A, Wang S. (2007) Inhibition of intestinal tumorigenesis in Apc(min/+) mice by green tea polyphenols (polyphenon E) and individual catechins. Nutr Cancer.59(1):62-9.

Xiao H, Hao X, Simi B, Ju J, Jiang H, Reddy BS, Yang CS. (2008) Green tea polyphenols inhibit colorectal aberrant crypt foci (ACF) formation and prevent oncogenic changes in dysplastic ACF in azoxymethane-treated F344 rats. Carcinogenesis. 29(1):113-9.

Marín YE, Wall BA, Wang S, Namkoong J, Martino JJ, Suh J, Lee HJ, Rabson AB, Yang CS, Chen S, Ryu JH. (2007) Curcumin downregulates the constitutive activity of NF-kappaB and induces apoptosis in novel mouse melanoma cells. Melanoma Res. 17(5):274-83.

Bose M, Hao X, Ju J, Husain A, Park S, Lambert JD, Yang CS. (2007) Inhibition of tumorigenesis in ApcMin/+ mice by a combination of (-)-epigallocatechin-3-gallate and fish oil. J Agric Food Chem. 55(19):7695-700.

Ju J, Lu G, Lambert JD, Yang CS. (2007) Inhibition of carcinogenesis by tea constituents. Semin Cancer Biol. 17(5):395-402.

Li S, Sang S, Pan MH, Lai CS, Lo CY, Yang CS, Ho CT. (2007) Anti-inflammatory property of the urinary metabolites of nobiletin in mouse. Bioorg Med Chem Lett. 17(18):5177-81.

Lubet RA, Yang CS, Lee MJ, Hara Y, Kapetanovic IM, Crowell JA, Steele VE, Juliana MM, Grubbs CJ. (2007) Preventive effects of polyphenon E on urinary bladder and mammary cancers in rats and correlations with serum and urine levels of tea polyphenols. Mol Cancer Ther. 6(7):2022-8.

Sang S, Yang I, Buckley B, Ho CT, Yang CS. (2007) Autoxidative quinone formation in vitro and metabolite formation in vivo from tea polyphenol (-)-epigallocatechin-3-gallate: studied by real-time mass spectrometry combined with tandem mass ion mapping. Free Radic Biol Med. 43(3):362-71.

Lambert JD, Sang S, Lu AY, Yang CS. (2007) Metabolism of dietary polyphenols and possible interactions with drugs. Curr Drug Metab. 8(5):499-507. Review.

Lambert JD, Kwon SJ, Hong J, Yang CS. (2007) Salivary hydrogen peroxide produced by holding or chewing green tea in the oral cavity. Free Radic Res. 41(7):850-3.

Liu T, Zhang X, So CK, Wang S, Wang P, Yan L, Myers R, Chen Z, Patterson AP, Yang CS, Chen X. (2007) Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells. Carcinogenesis. 28(2):488-96.

Cai YC, So CK, Nie AY, Song Y, Yang GY, Wang LD, Zhao X, Kinzy TG, Yang CS. (2007) Characterization of genetic alteration patterns in human esophageal squamous cell carcinoma using selected microsatellite markers spanning multiple loci. Int J Oncol. 30(5):1059-67.

Hong J, Kwon SJ, Sang S, Ju J, Zhou JN, Ho CT, Huang MT, Yang CS. (2007) Effects of garcinol and its derivatives on intestinal cell growth: Inhibitory effects and autoxidation-dependent growth-stimulatory effects. Free Radic Biol Med. 42(8):1211-21.

Lambert JD, Sang S, Yang CS. (2007) Possible controversy over dietary polyphenols: Benefits vs risks. Chem Res Toxicol. 20(4):583-5.

Fang M, Chen D, Yang CS. (2007) Dietary polyphenols may affect DNA methylation. J Nutr. 137(1 Suppl):223S-228S.

Yuan JM, Gao YT, Yang CS, Yu MC. (2007) Urinary biomarkers of tea polyphenols and risk of colorectal cancer in the Shanghai Cohort Study. Int J Cancer. 120(6):1344-50.

Lu G, Liao J, Yang G, Reuhl KR, Hao X, Yang CS. (2006) Inhibition of adenoma progression to adenocarcinoma in a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis model in A/J mice by tea polyphenols and caffeine. Cancer Res. 66(23):11494-501.

Chen X, Sood S, Yang CS, Li N, Sun Z. (2006) Five-lipoxygenase pathway of arachidonic acid metabolism in carcino-genesis and cancer chemoprevention. Curr Cancer Drug Targets. 6(7):613-22. Review.

Lambert JD, Sang S, Hong J, Kwon SJ, Lee MJ, Ho CT, Yang CS. (2006) Peracetylation as a means of enhancing in vitro bioactivity and bioavailability of epigallocatechin-3-gallate. Drug Metab Dispos. 34(12):2111-6.

Yang CS. (2006) Dietary factors may modify cancer risk by altering xenobiotic metabolism and many other mechanisms. J Nutr. 136(10):2685S-6S.

Sang S, Ju J, Lambert JD, Lin Y, Hong J, Bose M, Wang S, Bai N, He K, Reddy BS, Ho CT, Li F, Yang CS. (2006) Wheat bran oil and its fractions inhibit human colon cancer cell growth and intestinal tumorigenesis in Apc(min/+) mice. J Agric Food Chem. 54(26):9792-7.

Zhu LR. Thomas PE. Lu G. Reuhl KR. Yang GY. Wang LD. Wang SL. Yang CS. He XY. Hong JY. (2006) CYP2A13 in human respiratory tissues and lung cancers: An immunohistochemical study with a new peptide-specific antibody. Drug Metab Dispos. 34(10):1672-6.

Yang CS. Lambert JD. Hou Z. Ju J. Lu G. Hao X. (2006) Molecular targets for the cancer preventive activity of tea polyphenols. Mol Carcinog. 45(6):431-5.

Lambert JD. Kim DH. Zheng R. Yang CS. (2006) Transdermal delivery of (-)-epigallocatechin-3-gallate. a green tea polyphenol. in mice. J Pharm Pharmacol. 58(5):599-604.

Sang S. Hou Z. Lambert JD. Yang CS. (2005) Redox properties of tea polyphenols and related biological activities. Antioxid Redox Signal. 7(11-12):1704-14.

Mizuno H. Cho YY. Zhu F. Ma WY. Bode AM. Yang CS. Ho CT. Dong Z. (2006) Theaflavin-3. 3'-digallate induces epidermal growth factor receptor downregulation. Mol Carcinog. 45(3):204-12.

Sang S. Lee MJ. Hou Z. Ho CT. Yang CS. (2005) Stability of tea polyphenol (-)-epigallocatechin-3-gallate and formation of dimers and epimers under common experimental conditions. J Agric Food Chem. 53(24):9478-84.

Sang S. Lambert JD. Hong J. Tian S. Lee MJ. Stark RE. Ho CT. Yang CS. (2005) Synthesis and structure identification of thiol conjugates of (-)-epigallocatechin gallate and their urinary levels in mice. Chem Res Toxicol. 18(11):1762-9.

Ju J. Hong J. Zhou JN. Pan Z. Bose M. Liao J. Yang GY. Liu YY. Hou Z. Lin Y. Ma J. Shih WJ. Carothers AM. Yang CS. (2005) Inhibition of intestinal tumorigenesis in Apcmin/+ mice by (-)-epigallocatechin-3-gallate. the major catechin in green tea. Cancer Res. 65(22):10623-31.

Lambert JD. Lee MJ. Diamond L. Ju J. Hong J. Bose M. Newmark HL. Yang CS. (2006) Dose-dependent levels of epigallocatechin-3-gallate in human colon cancer cells and mouse plasma and tissues. Drug Metab Dispos. 34(1):8-11.

Hong J. Sang S. Park HJ. Kwon SJ. Suh N. Huang MT. Ho CT. Yang CS. (2006) Modulation of arachidonic acid metabolism and nitric oxide synthesis by garcinol and its derivatives. Carcinogenesis. 27(2):278-86.

Fang MZ. Chen D. Sun Y. Jin Z. Christman JK. Yang CS. (2005) Reversal of hypermethylation and reactivation of p16INK4a. RARbeta. and MGMT genes by genistein and other isoflavones from soy. Clin Cancer Res. 11(19 Pt 1):7033-41.

Hou Z. Sang S. You H. Lee MJ. Hong J. Chin KV. Yang CS. (2005) Mechanism of action of (-)-epigallocatechin-3-gallate: auto-oxidation-dependent inactivation of epidermal growth factor receptor and direct effects on growth inhibition in human esophageal cancer KYSE 150 cells. Cancer Res. 65(17):8049-56.

Shen G. Xu C. Hu R. Jain MR. Nair S. Lin W. Yang CS. Chan JY. Kong AN. (2005) Comparison of (-)-epigallocatechin-3-gallate elicited liver and small intestine gene expression profiles between C57BL/6J mice and C57BL/6J/Nrf2 (-/-) mice. Pharm Res. 22(11):1805-20.

Nguyen T. Sherratt PJ. Nioi P. Yang CS. Pickett CB. (2005) Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J Biol Chem. 280(37):32485-92.

Sood S. Shiff SJ. Yang CS. Chen X. (2005) Selection of topically applied non-steroidal anti-inflammatory drugs for oral cancer chemoprevention. Oral Oncol. 41(6):562-7.

Chen D. Wang CY. Lambert JD. Ai N. Welsh WJ. Yang CS. (2005) Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure-activity relationship and molecular-modeling studies. Biochem Pharmacol. 69(10):1523-31.

Seril DN. Liao J. Yang CS. Yang GY. (2005) Systemic iron supplementation replenishes iron stores without enhancing colon carcinogenesis in murine models of ulcerative colitis: comparison with iron-enriched diet. Dig Dis Sci. 50(4):696-707.

Lu YP. Lou YR. Liao J. Xie JG. Peng QY. Yang CS. Conney AH. (2005) Administration of green tea or caffeine enhances the disappearance of UVB-induced patches of mutant p53 positive epidermal cells in SKH-1 mice. Carcinogenesis. 26(8):1465-72.

Yang CS. Liao J. Yang GY. Lu G. (2005) Inhibition of lung tumorigenesis by tea. Exp Lung Res. 31(1):135-44.

Li N. Sood S. Wang S. Fang M. Wang P. Sun Z. Yang CS. Chen X. (2005) Overexpression of 5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of zileuton and celecoxib. Clin Cancer Res. 11(5):2089-96.

Lambert JD. Chen D. Wang CY. Ai N. Sang S. Ho CT. Welsh WJ. Yang CS. (2005) Benzotropolone inhibitors of estradiol methylation: kinetics and in silico modeling studies. Bioorg Med Chem. 13(7):2501-7.

Fang MZ. Jin Z. Wang Y. Liao J. Yang GY. Wang LD. Yang CS. (2005) Promoter hypermethylation and inactivation of O(6)-methylguanine-DNA methyltransferase in esophageal squamous cell carcinomas and its reactivation in cell lines. Int J Oncol. 26(3):615-22.

Lambert JD. Rice JE. Hong J. Hou Z. Yang CS. (2005) Synthesis and biological activity of the tea catechin metabolites. M4 and M6 and their methoxy-derivatives. Bioorg Med Chem Lett. 15(4):873-6.

Lambert JD. Hong J. Yang GY. Liao J. Yang CS. (2005) Inhibition of carcinogenesis by polyphenols: evidence from laboratory investigations. Am J Clin Nutr. 81(1 Suppl):284S-291S.

Yang CS. Hong J. Hou Z. Sang S. (2004) Green tea polyphenols: antioxidative and prooxidative effects. J Nutr. 134(11):3181S.

Hou Z. Lambert JD. Chin KV. Yang CS. (2004) Effects of tea polyphenols on signal transduction pathways related to cancer chemoprevention. Mutat Res. 555(1-2):3-19.