3,3′-Diindolylmethane Enhances Taxotere-Induced Apoptosis in Hormone-Refractory Prostate Cancer Cells through Survivin Down-regulation

Survivin, a member of inhibitor of apoptosis family, is associated with both prostate cancer progression and drug resistance. Therefore, we hypothesized that survivin may play a potentially important role in hormone-refractory prostate cancer (HRPC) and bone metastatic disease; thus, targeting of survivin signaling could enhance therapeutic efficacy in prostate cancer. 3,3'-Diindolylmethane (DIM) has been known to have cancer chemoprevention activity. However, no information is available regarding the down-regulation of survivin by DIM, which could result in the chemosensitization of HRPC cells to Taxotere-induced killing. We investigated the effect of DIM alone or in combination with Taxotere using LNCaP and C4-2B prostate cancer cells. We observed that DIM enhanced Taxotere-induced apoptotic death in both cell lines. These enhancing effects were related to a decrease in survivin expression as well as androgen receptor and nuclear factor-kappa B (NF-kappa B) DNA-binding activity. We also found that knockdown of survivin expression by small interfering RNA transfection increased DIM-induced cell growth inhibition and apoptosis, whereas overexpression of survivin by cDNA transfection abrogated DIM-induced cell growth inhibition and apoptosis in both prostate cancer cells. Importantly, luciferase assays showed a significant reduction of survivin-Luc and NF-kappa B-Luc activity in prostate cancer cells exposed to DIM and Taxotere. Furthermore, combination treatment significantly inhibited C4-2B bone tumor growth, and the results were correlated with the down-regulation of survivin. From these results, we conclude that inactivation of survivin by DIM enhanced the therapeutic efficacy of Taxotere in prostate cancer in general, which could be useful for the treatment of HRPC and metastatic prostate cancer. [Cancer Res 2009;69(10):4468-75]