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.
1,1-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.
Lei
Ping
P
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030-3303, USA.
Abdelrahim
Maen
M
Cho
Sung Dae
SD
Liu
Shengxi
S
Chintharlapalli
Sudhakar
S
Safe
Stephen
S
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D024161:Collagen Type XI / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000201:enzymology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D013329:Structure-Activity Relationship; D051742:Transcription Factor CHOP / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C499319:COL11A2 protein, human; D024161:Collagen Type XI; C497249:DDIT3 protein, human; D007211:Indoles; D051742:Transcription Factor CHOP; D048031:JNK Mitogen-Activated Protein Kinases; C016392:3,3'-diindolylmethane