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

    Authors

    P. Lei; M. Abdelrahim; S. D. Cho; S. X. Liu; S. Chintharlapalli;S. Safe

    Comments

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    Abbreviated Journal Title

    Carcinogenesis

    Keywords

    ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; GAMMA-INDEPENDENT PATHWAYS; INDUCED APOPTOSIS; PROSTATE-CANCER; AGONISTS; DEATH; DIINDOLYLMETHANE; INDUCTION; METHANES; Oncology

    Abstract

    1,1-Bis(3'-indolyl)-1-(p-substituted phenyl) methanes (C-DIMs) activate the orphan receptors peroxisome proliferator-activated receptor g (PPARg) 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 PPARg, 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-Cp-PhF 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.

    Journal Title

    Carcinogenesis

    Volume

    29

    Issue/Number

    6

    Publication Date

    1-1-2008

    Document Type

    Article

    Language

    English

    First Page

    1139

    Last Page

    1147

    WOS Identifier

    WOS:000257398100008

    ISSN

    0143-3334

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