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1,1-Bis(3 -indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through activation of c-jun N-terminal kinase Lei P; Abdelrahim M; Cho SD; Liu S; Chintharlapalli S; Safe SCarcinogenesis 2008[Jun]; 29 (6): 1139-471,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) activate the orphan receptors peroxisome proliferator-activated receptor gamma (PPARgamma) and Nur77 and induce receptor-dependent and -independent apoptotic pathways in colon and other cancer cells. Structure-activity studies show that the p-bromo (DIM-C-pPhBr) and p-fluoro (DIM-C-pPhF) analogs, which exhibit minimal activation of Nur77 and PPARgamma, induce expression of CCAAT/enhancer-binding protein homologous protein (CHOP/GADD153) in colon cancer cells. Moreover, among a series of bromo and fluoro C-DIM analogs, their induction of CHOP was dependent on the position of the phenyl substituents (para >/= meta >/= ortho) and required a free indole group. DIM-C-pPhBr and DIM-C-pPhF not only induced CHOP but also activated death receptor 5 (CHOP dependent), cleavage of caspase 8 and poly (ADP ribose) polymerase (PARP) that is consistent with activation of the extrinsic pathway of apoptosis. These responses were associated with the activation of c-jun N-terminal kinase (JNK) pathway since inhibition of JNK inhibited induction of the extrinsic apoptotic pathway by these C-DIMs. However, in contrast to classical inducers of endoplasmic reticulum (ER) stress such as tunicamycin and thapsigargin, the C-DIM compounds did not induce glucose-related protein 78 that is a marker of ER stress. Proapoptotic and anticarcinogenic effects were also observed in athymic nude mice bearing RKO cell xenografts and treated with 30 mg/kg/day DIM-C-pPhBr and this was accompanied by increased JNK phosphorylation in the tumors. Thus, the anticarcinogenic activity of DIM-C-pPhBr in colon cancer cells and tumors is related to a novel ER stress-independent activation of JNK.|Animals[MESH]|Antineoplastic Agents/chemistry/*pharmacology[MESH]|Blotting, Western[MESH]|Cell Line, Tumor[MESH]|Collagen Type XI/drug effects/metabolism[MESH]|Colonic Neoplasms/*enzymology[MESH]|Endoplasmic Reticulum/drug effects/metabolism/pathology[MESH]|Enzyme Activation/*drug effects[MESH]|Humans[MESH]|Immunohistochemistry[MESH]|Immunoprecipitation[MESH]|Indoles/chemistry/*pharmacology[MESH]|JNK Mitogen-Activated Protein Kinases/*drug effects/metabolism[MESH]|Mice[MESH]|Mice, Nude[MESH]|Structure-Activity Relationship[MESH]|Transcription Factor CHOP/drug effects/metabolism[MESH]|Transfection[MESH]|Xenograft Model Antitumor Assays[MESH] |
