Carcinogenesis Advance Access published online on May 5, 2008
Carcinogenesis, 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
2 Cancer Research Institute, M.D. Anderson Cancer Center - Orlando, Orlando, FL 32806
3 Burnett College of Biomedical Sciences, University of Central Florida, Orlando, FL 32816
4 Department of Oral Biology, School of Dentistry, Institute of Oral Biosciences, Chonbuk National University, Jeonju, Republic of Korea
5 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466
Correspondence should be sent to: Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466 USA, Tel: 979-845-5988 / Fax: 979-862-4929 / Email: ssafe{at}cvm.tamu.edu
1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)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 (DR5) (CHOP-dependent), cleavage of caspase 8 and PARP which is consistent with activation of the extrinsic pathway of apoptosis. These responses were associated with 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 (GRP78) which 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/d 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.
Key Words: C-DIMs • growth inhibition • colon cancer • JNK activation • apoptosis
Received January 24, 2008; revised April 22, 2008; accepted April 24, 2008.
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