3,3′-Diindolylmethane Enhances the Efficacy of Butyrate in Colon Cancer Prevention through Down-Regulation of Survivin

Abstract

Butyrate is an inhibitor of histone deacetylase (HDAC) and has been extensively evaluated as a chemoprevention agent for colon cancer. We recently showed that mutations in the adenomatous polyposis coli (APC) gene confer resistance to HDAC inhibitor-induced apoptosis in colon cancers. Here, we show that APC mutation rendered colon cancer cells resistant to butyrate-induced apoptosis due to the failure of butyrate to down-regulate survivin in these cells. Another cancer-preventive agent, 3,3′-diindolylmethane (DIM), was identified to be able to down-regulate survivin in colon cancers expressing mutant APC. DIM inhibited survivin mRNA expression and promoted survivin protein degradation through inhibition of p34 cdc2 -cyclin B1-mediated survivin Thr 34 phosphorylation. Pretreatment with DIM enhanced butyrate-induced apoptosis in colon cancer cells expressing mutant APC. DIM/ butyrate combination treatment induced the expression of proapoptotic Bax and Bak proteins, triggered Bax dimerization/activation, and caused release of cytochrome c and Smac proteins from mitochondria. Whereas overexpression of survivin blocked DIM/butyrateinduced apoptosis, knocking down of survivin by small interfering RNA increased butyrateinduced apoptosis in colon cancer cells. We further showed that DIM was able to downregulate survivin and enhance the effects of butyrate in apoptosis induction and prevention of familial adenomatous polyposis in APC min/+ mice. Thus, the combination of DIM and butyrate is potentially an effective strategy for the prevention of colon cancer.

Activation of Checkpoint Kinase 2 by 3,3′-Diindolylmethane Is Required for Causing G2/M Cell Cycle Arrest in Human Ovarian Cancer Cells

“…3,3Ј-Diindolylmethane (DIM) is an active metabolite of indole-3-carbinol present in cruciferous vegetables such as cabbage, broccoli, and kale (Grose and Bjeldanes, 1992). Previous studies have indicated that DIM has antiproliferative activity against various cancers (Hong et al, 2002a;Chen et al, 2006;Rahman et al, 2006;Kong et al, 2007;Bhatnagar et al, 2009). DIM has been shown to suppress cancer growth by inhibiting oncogenic molecules such as nuclear factor-B, Akt, and ␤-catenin in breast and prostate cancers (Chen et al, 2006;Rahman et al, 2006;Kong et al, 2007).…”

Effect of horse chestnut and inulin as single supplements or in combination on chemically induced colon cancer in rats

“…The diet with prebiotics decreased caecal pH which is the result of increased production of SCFA from carbohydrate fermentation. The treatment with prebiotics caused the highest increase in butyrate, a compound which has been demonstrated to have anti-tumour effects (Bhatnagar et al 2009). The diet with plant extract alone and in combination with prebiotics increased the caecal pH compared to the control group.…”

Indoles as anticancer agents

“…CIAPs, X-chromosome linked inhibitor of apoptose protein (XIAP) and survival, (c): up-regulation of pro-apoptotic factors such as Bax gene, (d): liberation of mitochondrial cytochrome C in addition to stimulating of caspase-9 and caspase-3 [45] , and (e): inhibition of the NF-k B signaling pathway [46][47][48][49][50][51] . A vast number of diverse mechanisms of apoptosis induction by indoles have also been reported [52][53][54][55][56] . Figure 8 demonstrates the extrinsic and the intrinsic pathways of apoptosis (programmed cell death).…”