title: A potent indole-3-carbinol derived antitumor agent with pleiotropic effects on multiple signaling pathways in prostate cancer cells.
abstract: Indole-3-carbinol has emerged as a promising chemopreventive agent due to its in vivo efficacy in various animal models. However, indole-3-carbinol exhibits weak antiproliferative potency and is unstable in acidic milieu. Thus, this study was aimed at exploiting indole-3-carbinol to develop potent antitumor agents with improved chemical stability. This effort culminated in OSU-A9 {[1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol}, which is resistant to acid-catalyzed condensation, and exhibits 100-fold higher apoptosis-inducing activity than the parent compound. Relative to indole-3-carbinol, OSU-A9 displays a striking qualitative similarity in its effects on the phosphorylation or expression of multiple signaling targets, including Akt, mitogen-activated protein kinases, Bcl-2 family members, survivin, nuclear factor-kappaB, cyclin D1, p21, and p27. The ability of OSU-A9 to concurrently modulate this broad range of signaling targets underscores its in vitro and in vivo efficacy in prostate cancer cells. Nevertheless, despite this complex mode of mechanism, normal prostate epithelial cells were less susceptible to the antiproliferative effect of OSU-A9 than PC-3 and LNCaP prostate cancer cells. Treatment of athymic nude mice bearing established s.c. PC-3 xenograft tumors with OSU-A9 at 10 and 25 mg/kg i.p. for 42 days resulted in a 65% and 85%, respectively, suppression of tumor growth. Western blot analysis of representative biomarkers in tumor lysates revealed significant reductions in the intratumoral levels of phosphorylated (p-) Akt, Bcl-xL, and RelA, accompanied by robust increases in p-p38 levels. In conclusion, the ability of OSU-A9 to target multiple aspects of cancer cell survival with high potency suggests its clinical value in prostate cancer therapy.
authors: Department of Biological Science and Technology, China Medical University, Taiwan.
authors: Jing-Ru
authors: JR
authors: Weng
authors: Chen-Hsun
authors: CH
authors: Tsai
authors: Samuel K
authors: SK
authors: Kulp
authors: Dasheng
authors: D
authors: Wang
authors: Chia-Hui
authors: CH
authors: Lin
authors: Hsiao-Ching
authors: HC
authors: Yang
authors: Yihui
authors: Y
authors: Ma
authors: Aaron
authors: A
authors: Sargeant
authors: Chang-Fang
authors: CF
authors: Chiu
authors: Ming-Hsui
authors: MH
authors: Tsai
authors: Ching-Shih
authors: CS
authors: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D019281:Dimerization; D004355:Drug Stability; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D000432:Methanol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C523234:(1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl)-methanol; D000970:Antineoplastic Agents; D007211:Indoles; C016517:indole-3-carbinol; D000432:Methanol