Activation of Nerve Growth Factor-Induced Bα by Methylene-Substituted Diindolylmethanes in Bladder Cancer Cells Induces Apoptosis and Inhibits Tumor Growth

• DOI: 10.1124/mol.109.061143
• Publication Date: 2009-12-19T02:32:29Z
• Authors: Sung Dae Cho; Syng-Ook Lee; Sudhakar Chinthar...; Maen Abdelrahim; Shaheen Khan; Kyungsil Yoon; Ashish M. Kamat; Stephen Safe
• Keywords: Male; 0301 basic medicine; Indoles; Mice, Nude; Antineoplastic Agents; Apoptosis; Growth Inhibitors; 3. Good health; Mice; Random Allocation; 03 medical and health sciences; Urinary Bladder Neoplasms; Cell Line, Tumor; Nuclear Receptor Subfamily 4, Group A, Member 1; Animals; Humans

Nerve growth factor-induced B (NGFI-B) genes are orphan nuclear receptors, and NGFI-Bα (Nur77, TR3) is overexpressed in bladder tumors cancer cells compared with nontumorous tissue. 1,1-Bis(3′-indolyl)-1-(<i>p</i>-methoxyphenyl)-methane (DIM-C-pPhOCH₃) 1,1-bis(3′-indolyl)-1-(<i>p</i>-phenyl)methane have previously been identified as activators of Nur77, both compounds inhibited induced apoptosis UC-5 KU7 cells. The proapoptotic effects methylene-substituted diindolylmethanes (C-DIMs) were unaffected by cotreatment leptomycin dependent on RNA interference a small inhibitory for Nur77 (iNur77) demonstrated that C-DIM-induced activation was Nur77-dependent. Microarray analysis DIM-C-pPhOCH₃-induced showed this compound multiple Nur77-dependent or including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), cystathionase, p21, p8, sestrin-2. DIM-C-pPhOCH₃ (25 mg/kg/d) also athymic nude mice bearing xenografts, demonstrating Nur77-active C-DIMs exhibit potential chemotherapy targeting which type.