Carcinogenesis Advance Access originally published online on May 5, 2008
Carcinogenesis 2008 29(6):1139-1147; doi:10.1093/carcin/bgn103
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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
1 Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030-3303, USA
2 Cancer Research Institute, M.D. Anderson Cancer Center—Orlando, Orlando, FL 32806, USA
3 Burnett College of Biomedical Sciences, University of Central Florida, Orlando, FL 32816, USA
4 Department of Oral Biology, School of Dentistry, Institute of Oral Biosciences, Chonbuk National University, Jeonju, Republic of Korea 561-756
5 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA
* To whom correspondence should be addressed. Tel: +1 979 845 5988; Fax: +1 979 862 4929; Email: ssafe{at}cvm.tamu.edu
1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) activate the orphan receptors peroxisome proliferator-activated receptor 
(PPAR) 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 PPAR, 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.
Abbreviations: ASK1, apoptosis signal-regulating kinase-1; C-DIM, 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methane; DIM, diindolylmethane; DMSO, dimethyl sulfoxide; DR5, death receptor 5; ER, endoplasmic reticulum; GRP78, glucose-related protein 78; JNK, c-jun N-terminal kinase; PARP, poly (ADP-ribose) polymerase; PBS, phosphate-buffered saline; PPAR, peroxisome proliferator-activated receptor ; Tg, Thapsigargin; Tm, Tunicamycin
Received January 24, 2008; revised April 22, 2008; accepted April 24, 2008.