A promising new
treatment for prostate cancer is indole-3-carbinol (I3C). Indole-3-carbinol is a biologically active compound
found in cruciferous vegetables such as brussel sprouts, cabbage and broccoli. It is converted into the active compound 3,3'-diindolylmethane (DIM) in the stomach. The molecular mechanisms underlying the anticarcinogenic actions of I3C and DIM are now being elucidated.Both I3C and DIM inhibit prostate cell growth in a dose- and time-dependent manner. This effect may be due to Cyclin-dependent kinase (CDK) 6 downregulation and upregulation of p21WAF1 and p27KIP1. In addition, I3C inhibits CDK6 activity. These actions may contribute to cessation of prostate cancer cell division in the G1 phase.Indole-3-carbinol also kills cancer cells by induction of
apoptosis.
Treatment of prostate cancer cells for 24 hours with I3C in vitro increases the Bax to Bcl-2 ratio which is a marker of apoptotic activity. The same cells undergo apoptosis after 48 hours. The active DIM metabolite also induces apoptosis in prostate cancer cells. In breast cancer cells, I3C causes apoptosis by translocating the apoptotic protein bax from the cytosol to the mitochondria. Apoptosis is triggered by the subsequent loss of mitochondrial membrane potential and release of cytochrome c.Indole-3-carbinol inhibits the anti-apoptotic nuclear factor-B (NF-B) and akt pathways in prostate cancer cells. It inhibits NF-B DNA binding and consequently reduces cell proliferation and induces apoptosis. Inhibition of NF-B, akt kinase and downregulation of phosphatidylinositol-3 kinase expression describe some of the effects of I3C on the akt pathway. By targeting these pathways I3C and DIM could sensitize cancer cells to chemotherapy and offer more effective cancer treatment. Indeed, co-treatment of prostate cancer cells with cisplatin and I3C inhibits cell growth more than does each treatment alone.Microarray analysis has provided insight into how I3C and DIM regulate gene expression in prostate cancer cells. These results will help identify molecular targets for chemotherapeutic agents. Both I3C and DIM downregulate expression of transforming-growth factor and other cell growth promoters as well as anti-apoptic proteins such as cyclin E2. Predictably, these compounds downregulate other genes that are associated with transcription and oncogenesis (ie TFDP1 and NF-YC). While the in vitro evidence shows that I3C and DIM are anticarcinogenic, further in vitro and invivo studies are needed to elucidate fully their therapeutic value.