Project 176577

Numerous studies have shown the protective effects against cancer of high vegetable consumption, particularly that of cruciferous vegetables of the Brassica family (broccoli, cauliflower, cabbage). These vegetables contain high amounts of indole-3-carbinol (I3C), which is converted in the body to the metabolite diindolylmethane (DIM). DIM is a more potent anti-cancer agent than I3C, and studies have shown that it is effective against a variety of cancers, including that of the prostate. Hormone-dependent prostate tumors grow under the influence of the potent male sex hormone dihydrotestosterone (DHT). Current treatment of these prostate tumors involves drugs that block the action of DHT on the androgen receptor (AR antagonists), or those that prevent the synthesis of DHT by inhibiting the enzyme steroid 5-alpha-reductase (SRD5A inhibitors). DIM acts as an AR antagonists and this is thought to be one possible way in which it inhibits prostate cancer growth. Preliminary results using cancer cell lines (in vitro) suggest that a group of synthetic derivatives of DIM, called ring-DIMs, have more potent anticancer properties than DIM. Furthermore, these ring-DIMs appear to be effective against hormone-dependent as well as -independent prostate cancer cells. This suggests that they are excellent candidates for detailed studies of their mode of anti-prostate cancer action and biological effectiveness in vivo. The present research proposal wishes to determine whether ring-DIMs are effective in vivo by testing their anticancer activity in mice that carry bioluminescent human prostate tumor cells (xenografts). These cells produce light, allowing for location and growth of the tumor to be easily monitored using an imager, without the need to sacrifice the animals periodically to assess tumor progression. Experiments using prostate cancer cell lines in culture will assess various mechanisms of anticancer action to better understand how ring-DIMs work in tumor cells.