Ah-Ng Tony Kong Professor Rutgers University Department of Pharmaceutics Ernest Mario School of Pharmacy. Room 228 Piscataway. NJ 08854 (732) 445-3831. Ext 228 FAX - 3134 kongt@rci.rutgers.edu

Pharmaceutical Biotechnology. Pharmacogenomics and toxicogenomics of cancer chemopreventive compounds. MAP Kinases / Nrf2 transcription factor - mediated gene expression. and pharmacokinetics. pharmacodyanmics and drug metabolism of drugs

Many naturally occurring cancer chemopreventive compounds can modulate signal transduction events leading to gene expression and prevention of cancer. The research of my laboratory is to study two important cellular signaling pathways. the mitogen-activated protein kinases (MAPKs) and the caspases pathways activated by these compounds as well as environmental agents and chemotherapeutic drugs. One of the downstream targets that are modulated by chemochemopreventive agents-induced MAPK signaling is the bZIP transcription factors Nrf2/Maf which induce cellular defensive enzymes via the antioxidant response element (ARE). Our lab had shown that various MAPK proteins modulate the transcriptional activity of Nrf2 on ARE-luciferase reporter gene leading gene to expression of cellular defense enzymes such as heme-oxygenase-1 and Phase II drug metabolizing enzymes. Our approach to investigate various chemopreventive agents are to combine biochemical and molecular biology in cell cultures combined with appropriate in vivo animal animal models for human cancers of colon and prostate. Ongoing projects focus on: (i) Chemoprevention of cancer: Preclinical and clinical studies of chemopreventive agents; (ii) Drug metabolism: Biochemistry. pharmacology and regulation of gene expression of drug metabolizing enzymes (cytochrome P450s and phase II enzymes) in relationship to carcinogenesis and chemoprevention; (iii) Cellular signal transduction: MAPK; ERK. JNK. p38 in regulation of gene expression in cell survival and apoptosis; (iv) Apoptosis: Role of caspases. TRAIL and death receptors (DRs) in apoptosis; (v) Pharmacokinetics. and pharmacodynamics of anti-cancer drugs (preventive and chemotherapeutics) and environmental agents; and (vi) Prostate cancer: Biology. signaling. prevention and therapy.

Selected Publications

Nair S, Li W, Kong AN. (2007) Natural dietary anti-cancer chemopreventive compounds: redox-mediated differential signaling mechanisms in cytoprotection of normal cells versus cytotoxicity in tumor cells. Acta Pharmacol Sin. 28(4):459-72.

Shen G, Hong JL, Kong AN. (2007) Development and validation of an HPLC method for the determination of dibenzoylmethane in rat plasma and its application to the pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. Jan 10; [Epub ahead of print]

Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, Kong AN. (2006) Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res. 66(24):11580-4.

Nair S, Xu C, Shen G, Hebbar V, Gopalakrishnan A, Hu R, Jain MR, Liew C, Chan JY, Kong AN. (2007) Toxicogenomics of endoplasmic reticulum stress inducer tunicamycin in the small intestine and liver of Nrf2 knockout and C57BL/6J mice. Toxicol Lett. 168(1):21-39.

Hu R, Shen G, Yerramilli UR, Lin W, Xu C, Nair S, Kong AN. (2006) In vivo pharmacokinetics, activation of MAPK signaling and induction of phase II/III drug metabolizing enzymes/transporters by cancer chemopreventive compound BHA in the mice. Arch Pharm Res. 29(10):911-20.

Keum YS, Han YH, Liew C, Kim JH, Xu C, Yuan X, Shakarjian MP, Chong S, Kong AN.(2006)
Induction of heme oxygenase-1 (HO-1) and NAD[P]H: quinone oxidoreductase 1 (NQO1) by a phenolic antioxidant, butylated hydroxyanisole (BHA) and its metabolite, tert-butylhydroquinone (tBHQ) in primary-cultured human and rat hepatocytes. Pharm Res. 23(11):2586-94.

Nair S, Xu C, Shen G, Hebbar V, Gopalakrishnan A, Hu R, Jain MR, Lin W, Keum YS, Liew C, Chan JY, Kong AN. (2006) Pharmacogenomics of phenolic antioxidant butylated hydroxyanisole (BHA) in the small intestine and liver of Nrf2 knockout and C57BL/6J mice. Pharm Res. 23(11):2621-37.

Gopalakrishnan A, Xu CJ, Nair SS, Chen C, Hebbar V, Kong AN. (2006) Modulation of activator protein-1 (AP-1) and MAPK pathway by flavonoids in human prostate cancer PC3 cells.
Arch Pharm Res. 29(8):633-44.

Khor TO, Hu R, Shen G, Jeong WS, Hebbar V, Chen C, Xu C, Nair S, Reddy B, Chada K, Kong AN.
(2006) Pharmacogenomics of cancer chemopreventive isothiocyanate compound sulforaphane in the intestinal polyps of ApcMin/+ mice. Biopharm Drug Dispos. 27(9):407-20.

Keum YS, Yu S, Chang PP, Yuan X, Kim JH, Xu C, Han J, Agarwal A, Kong AN. (2006) Mechanism of action of Sulforaphane: Inhibition of p38 mitogen-activated protein kinase isoforms contributing to the induction of antioxidant response element-mediated Heme Oxygenase-1 in human hepatoma HepG2 cells. Cancer Res. 66(17):8804-13.

Xu C, Yuan X, Pan Z, Shen G, Kim JH, Yu S, Khor TO, Li W, Ma J, Kong AN. (2006) 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. 5(8):1918-26.

Mandlekar S, Hong JL, Kong AN. (2006) Modulation of metabolic enzymes by dietary phytochemicals: a review of mechanisms underlying beneficial versus unfavorable effects.
Curr Drug Metab. 7(6):661-75. Review.

Khor TO, Ibrahim S, Kong AN. (2006) Toxicogenomics in drug discovery and drug development: potential applications and future challenges. Pharm Res. 23(8):1659-64. Review.

Hu R, Xu C, Shen G, Jain MR, Khor TO, Gopalkrishnan A, Lin W, Reddy B, Chan JY, Kong AN. (2006) Identification of Nrf2-regulated genes induced by chemopreventive isothiocyanate PEITC by oligonucleotide microarray. Life Sci. 79(20):1944-55.

Li W, Yu SW, Kong AN. (2006) Nrf2 possesses a redox-sensitive nuclear exporting signal in the Neh5 transactivation domain. J Biol Chem. 281(37):27251-63.

Lin W. Shen G. Yuan X. Jain MR. Yu S. Zhang A. Chen JD. Kong AN. (2006) Regulation of Nrf2 transactivation domain activity by p160 RAC3/SRC3 and other nuclear co-regulators. J Biochem Mol Biol. 39(3):304-10.

Zheng X. Chang RL. Cui XX. Avila GE. Hebbar V. Garzotto M. Shih WJ. Lin Y. Lu SE. Rabson AB. Kong AN. Conney AH. (2006) Effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination with paclitaxel (Taxol) on prostate Cancer LNCaP cells cultured in vitro or grown as xenograft tumors in immunodeficient mice. Clin Cancer Res. 12(11 Pt 1):3444-51.

Jeong WS. Jun M. Kong AN. (2006) Nrf2: a potential molecular target for cancer chemoprevention by natural compounds. Antioxid Redox Signal. 8(1-2):99-106.

Shen G. Xu C. Hu R. Jain MR. Gopalkrishnan A. Nair S. Huang MT. Chan JY. Kong AN.(2006) Modulation of nuclear factor E2-related factor 2-mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin. Mol Cancer Ther. 5(1):39-51.

Khor TO. Keum YS. Lin W. Kim JH. Hu R. Shen G. Xu C. Gopalakrishnan A. Reddy B. Zheng X. Conney AH. Kong AN. (2006) Combined inhibitory effects of curcumin and phenethyl isothiocyanate on the growth of human PC-3 prostate xenografts in immunodeficient mice. Cancer Res. 66(2):613-21.

Kim JH. Xu C. Keum YS. Reddy B. Conney A. Kong AN. (2006) Inhibition of EGFR signaling in human prostate cancer PC-3 cells by combination treatment with beta-phenylethyl isothiocyanate and curcumin. Carcinogenesis. 27(3):475-82.

Xu C. Shen G. Yuan X. Kim JH. Gopalkrishnan A. Keum YS. Nair S. Kong AN. (2006) ERK and JNK signaling pathways are involved in the regulation of activator protein 1 and cell death elicited by three isothiocyanates in human prostate cancer PC-3 cells. Carcinogenesis. 27(3):437-45.

Shen G. Xu C. Chen C. Hebbar V. Kong AN. (2006) p53-independent G1 cell cycle arrest of human colon carcinoma cells HT-29 by sulforaphane is associated with induction of p21CIP1 and inhibition of expression of cyclin D1. Cancer Chemother Pharmacol. 57(3):317-27.

Chen C. Kong AN. (2005) Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects. Trends Pharmacol Sci. 26(6):318-26.

Xu C. Shen G. Chen C. Gelinas C. Kong AN. (2005) 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. 24(28):4486-95.

Xu C. Li CY. Kong AN. (2005) Induction of phase I. II and III drug metabolism/transport by xenobiotics. Arch Pharm Res. 28(3):249-68.

Jeong WS. Keum YS. Chen C. Jain MR. Shen G. Kim JH. Li W. Kong AN. (2005) Differential expression and stability of endogenous nuclear factor E2-related factor 2 (Nrf2) by natural chemopreventive compounds in HepG2 human hepatoma cells. J Biochem Mol Biol. 38(2):167-76.

Keum YS. Jeong WS. Kong AN. (2005) Chemopreventive functions of isothiocyanates. Drug News Perspect. 18(7):445-51.

Shen G. Jeong WS. Hu R. Kong AN. (2005) Regulation of Nrf2. NF-kappaB. and AP-1 signaling pathways by chemopreventive agents. Antioxid Redox Signal. 7(11-12):1648-63.

Jeong. W.-S.. Kim. I.-W.. Hu. R.. and Kong. A.-N.T. (2004). Modulatory properties of various natural chemopreventive agents on the activation of NF-kappaB signaling pathway. Pharmaceutical Research 21: 661-670.

Jeong. W.-S.. Kim. I.-W.. Hu. R.. and Kong. A.-N.T. (2004). Modulation of AP-1 by natural chemopreventive compounds in human HT-29 cancer cell line. Pharmaceutical Research 21: 649-660.

Hu. R.. and Kong. A.-N.T. (2004) Activation of MAP kinase. apoptosis and nutragenomic of gene expression elicited by dietary components. Nutrition. Jan;20(1):83-88. (Invited review).

Kim. B.-R.. Hu. R.. Keum. Y.-S.. Hebbar. V.. Shen. G. and Kong. A.-N.T. (2003). Effects of glutathione on antioxidant response element-mediated gene expression and apoptosis elicited by sulforaphane. Cancer Research 63: 7520-7525.

Keum. Y.. Owuor. E.D.. Kim. B.-R.. Hu. R. and Kong. A.-N.T. (2003). Involvement of Nrf2 and JNK in the activation of antioxidant responsive element (ARE) by phenethyl isothiocyanate (PEITC) chemopreventive agent. Pharmaceutical Research 20: 1351-1356.

Chen. C.. Shen. G.. Hebbar. V.. Hu. R.. Owuor. E.D.. and Kong. A.-N.T. (2003). Epigallocatechin-3-gallate-induced stress signals in HT-29 human colon adenocarcinoma cells. Carcinogenesis 24:1369-1378.

Hu. R.. Chen. C.. Kim. B.R.. and Kong. A.-N.T. (2003). The roles of JNK and apoptotic signaling pathways in PEITC-mediated pharmacodynamics responses in human HT-29 colon cancer cells. Carcinogenesis 24: 1361-1367.

Misra. P.. Owuor. E.D.. Li. W.. Yu. S.. Qi. C.. Meyer. K.. Zhu. Y.-J.. Rao. M.S.. Kong. A.-N.T. and Reddy. J.K. (2002). Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP). Stimulation of Transcriptional Regulation by Mitogen-activated Protein Kinase. J. Biol. Chem. 277(50):48745-54.

Chen. Y.-R.. Han. J.. Kori. R.. Kong. A.-N.T. and Tan. T.-H. (2002). Phenylethyl isothiocyanate induces apoptotic signaling via suppressing phosphatase activity against c-Jun N-terminal kinase. J. Biol. Chem. 277:39334-39342.

Rushmore. T.H. and Kong. A.-N.T. (2002). Pharmacogenomics. regulation and signaling pathways for phase I and II drug metabolizing enzymes (Invited Review) Current Drug Metabolism 3: 481-490.

Owour. E. and Kong. A.-N.T. Owour. E. and Kong. A.-N.T. (2002). Antioxidants and Oxidants Regulated Signal Transduction Pathways. (Symposium on Cell Signaling. transcription and translation as therapeutic targets. January 30-February 2. 2002. Kirchberg. Luxembourg) (Invited Review). Biochemical Pharmacology 64: 765-770.