title: In vivo pharmacodynamics of indole-3-carbinol in the inhibition of prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) mice: involvement of Nrf2 and cell cycle/apoptosis signaling pathways.
abstract: Indole-3-carbinol (I3C) found abundantly in crucifers has been shown to possess anti-cancer effects. The present study aims to examine the chemopreventive effects and the molecular mechanism of I3C, particularly the anti-oxidative stress pathway regulated by nuclear erythroid related factor 2 (Nrf2). HepG2-C8-ARE-luciferase cells were used for Nrf2-ARE activity. TRAMP C1 cells were used to investigate the effects of I3C on Nrf2-mediated genes. To test the chemopreventive efficacy of I3C, transgenic adenocarcinoma of mouse prostate (TRAMP) mice were fed with 1% I3C supplemented diet for 12 or 16 wk. The expression of Nrf2 and its downstream target genes, cell cycle and apoptosis genes were investigated using quantitative real-time polymerase chain reaction (qPCR). The protein expressions of these biomarkers were also investigated using Western blotting. I3C induced antioxidant response element (ARE)-luciferase activity in a dose-dependent manner. Treatments of TRAMP C1 cells with I3C also resulted in the induction of Nrf2-mediated genes. I3C significantly suppressed the incidence of palpable tumor and reduced the genitourinary weight in TRAMP mice. Western blots and qPCR analyses of prostate tissues showed that I3C induced the expression of Nrf2, NAD(P)H quinine oxidoreductase 1 (NQO-1) as well as cell cycle and apoptosis related biomarkers in I3C-fed TRAMP mice. This study demonstrated that the effectiveness of I3C as prostate cancer chemoprevention agent via up-regulation of a novel Nrf2-mediated anti-oxidative stress pathway.
authors.affiliation: Center for Cancer Prevention Research and Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
authors.forename: Tien-Yuan
authors.initials: TY
authors.lastname: Wu
authors.forename: Constance Lay-Lay
authors.initials: CL
authors.lastname: Saw
authors.forename: Tin Oo
authors.initials: TO
authors.lastname: Khor
authors.forename: Douglas
authors.initials: D
authors.lastname: Pung
authors.forename: Sarandeep S S
authors.initials: SS
authors.lastname: Boyanapalli
authors.forename: Ah-Ng Tong
authors.initials: AN
authors.lastname: Kong
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D019587:Dietary Supplements; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D020218:Response Elements / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D007211:Indoles; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C016517:indole-3-carbinol; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse