Abstract A33: Superior efficacy of dietary 3,3’diindolylmethane (DIM) amongst several indoles to inhibit prostate cancer growth via induction of the p75NTR tumor suppressor protein

Abstract

Abstract A33 A comparison of the indoles etodolac, indomethacin, 5-methylindole-3-acetic acid, indole-3-carbinol, 3,3’diindolylmethane (DIM) and the related ketorolac molecule showed superior efficacy of DIM, a dietary indole, to induce expression of the p75NTR tumor suppressor and inhibit survival of the PC-3 prostate cancer cell line. Each indole that induced p75NTR expression exhibited the same rank-order for inhibition of prostate cell survival. Comparison of the activity of DIM, the most potent of the indoles, between several cell lines, showed that DIM induced p75NTR at low concentrations in prostate cells (PC-3 , DU-145), followed by bladder (T24), with breast (MCF-7) and fibroblast cells (3T3) being the least responsive to DIM. DIM induction of p75NTR levels in the various cell lines occurred in the same rank-order as inhibition of cell survival. Since the consumption of cruciferous vegetables has been reported to reduce the risk of prostate cancer through the release of indole-3-carbinol (I3C) which is subsequently metabolized in the acidic environment of the stomach to DIM, the superior activity of DIM to induce expression of the p75NTR tumor suppressor protein and inhibit cell survival suggests a mechanism of action for the anticancer activity of DIM in the prevention of prostate cancer. In order to demonstrate a cause and effect between DIM and p75NTR inhibition of survival, we used a dominant negative of p75NTR to rescue DIM induced loss of cell survival. In order to investigate the mechanism of action by which p75NTR transduces a biochemical signaling cascade leading to cell death of prostate cancer cells we utilized knockdown with p38 MAPK siRNA to rescue DIM induction of p75NTR thereby implicating p38 MAPK in DIM induction of cell death. Moreover, DIM treatment induced phosphorylation of p38 MAPK within one minute, suggesting the target of DIM is proximal to p38 MAPK. Hence, these results suggest that the anti-cancer activity of cruciferous vegetables may be mediated in part by DIM and that the mechanism of action occurs, in part, by activation of the p38 MAPK pathway leading to expression of the p75NTR death receptor with subsequent apoptosis of prostate cancer cells. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A33.