1,1-Bis(3′-indolyl)-1-(p-bromophenyl)methane and related compounds repress survivin and decrease γ-radiation-induced survivin in colon and pancreatic cancer cells

Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA.
International Journal of Oncology (Impact Factor: 3.03). 11/2009; 35(5):1191-9. DOI: 10.3892/ijo_00000436
Source: PubMed


1,1-Bis(3'-indolyl)-1-(p-bromophenyl)methane (DIM-C-pPhBr) and the 2,2'-dimethyl analog (2,2'-diMeDIM-C-pPhBr) inhibit proliferation and induce apoptosis in SW480 colon and Panc28 pancreatic cancer cells. In this study, treatment with 10-20 microM concentrations of these compounds for 24 h induced cleaved PARP and decreased survivin protein and mRNA expression in both cell lines. However, results of time course studies show that DIM-C-pPhBr and 2,2'-diMeDIM-C-pPhBr decrease survivin protein within 2 h after treatment, whereas survivin mRNA levels were decreased only at later time-points indicating activation of transcription-independent and -dependent pathways for downregulation of survivin. In addition, we also observed that gamma-radiation inhibited pancreatic and colon cancer cell growth and this was associated with enhanced expression of survivin after 24 (SW480) or 24 and 48 h (Panc28) and correlated with previous studies on the role of survivin in radiation-resistance. However, in cells co-treated with gamma-radiation plus DIM-C-pPhBr or 2,2'-diMeDIM-C-pPhBr, induction of survivin by gamma-radiation was inhibited after co-treatment with both compounds, suggesting applications for these drugs in combination cancer chemotherapy with gamma-radiation.

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    • "Similarly, in colon cancer cells there is evidence to indicate down-regulation of survivin by DIM [64]. Further, synthetic analogs of DIM (DIM-C-pPhBr and 2,2′-diMeDIM-C-pPhBr) have also been shown to induce apoptosis in various cancer cells through down-regulation of survivin at both mRNA and protein expression levels [93]. Thus, there is ample evidence to suggest that indole compounds such as DIM, and its analogs, effectively down-regulate survivin which serves as one important mechanism responsible for their apoptosis-inducing activity. "
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    ABSTRACT: Indole compounds, obtained from cruciferous vegetables, are well-known for their anti-cancer properties. In particular, indole-3-carbinol (I3C) and its dimeric product, 3,3´-diindolylmethane (DIM), have been widely investigated for their effectiveness against a number of human cancers in vitro as well as in vivo. These compounds are effective inducers of apoptosis and the accumulating evidence documenting their ability to modulate multiple cellular signaling pathways is a testimony to their pleiotropic behavior. Here we attempt to update current understanding on the various mechanisms that are responsible for the apoptosis-inducing effects by these compounds. The significance of apoptosis-induction as a desirable attribute of anti-cancer agents such as indole compounds cannot be overstated. However, an equally intriguing property of these compounds is their ability to sensitize cancer cells to standard chemotherapeutic agents. Such chemosensitizing effects of indole compounds can potentially have major clinical implications because these non-toxic compounds can reduce the toxicity and drug-resistance associated with available chemotherapies. Combinational therapy is increasingly being realized to be better than single agent therapy and, through this review article, we aim to provide a rationale behind combination of natural compounds such as indoles with conventional therapeutics.
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    • "Survivin is a member of the IAP gene family whose expression is associated with conservation of cell division and direct inhibition of caspases (Altieri, 2006). Upregulation of survivin expression has been shown in glioblastoma, colon, and pancreatic cells (Chakravarti et al., 2004; Sreevalsan et al., 2009). Intratumoral injection of an antisense against survivin or of an adenovirus expressing a dominant negative form of survivin, T34A, inhibits tumor growth and enhances sensitivity to anti-androgen therapy (O'Connor et al., 2000; Zhang et al., 2005). "
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    ABSTRACT: Indole compounds, obtained from cruciferous vegetables, have been investigated for their putative anti-cancer properties. Studies with indole-3-carbinol (I3C) and its dimeric product, 3, 3' diindolylmethane (DIM), have indicated efficacy of these compounds against a number of human cancers. Available as well as emerging data suggests that these compounds act on a number of cellular signaling pathways leading to their observed biological effects. Such pleiotropic effects of these compounds are also considered crucial for their chemosensitization activity wherein they help reduce the toxicity and resistance against conventional chemotherapeutic drugs. These observations have major clinical implications especially in chemotherapy. Through this review, we have attempted to update current understanding on the state of anti-cancer research involving indole compounds. We have also summarized the available literature on modulatory effects of indoles on molecular targets such as survivin, uPA/uPAR and signaling pathways such as the NF-kappaB pathway, which are important for the apoptosis-inducing and chemosensitizing properties of these compounds.
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