Targeting Survivin by 3, 3'-Diindolylmethane (DIM) for Prostate Cancer Therapy; Annual rept. 15 Mar 2007-14 Mar 2008

摘要

There is accumulating evidence suggesting that survivin, a member of the inhibitor of apoptosis (IAP) family, is associated with both progression of prostate carcinoma and drug resistance. Therefore, we hypothesized that survivin plays a role in the development of hormone-refractory prostate cancer (HRPC) and resists killing by chemotherapeutic agents; thus the down-regulation of survivin by DIM, a non-toxic dietary compound formed in the stomach after consumption of Brassica vegetables like broccoli or cabbage, has been known to have cancer chemopreventive activity with greater bioavailability could enhance killing of hormone insensitive prostate cancer cells by Taxotere. Recently, we discovered that DIM-induced apoptosis is associated with downregulation of survivin in breast cancer cells. We also found that DIM significantly sensitized the breast cancer cells to Taxotere-induced killing. Therefore, we would like to test whether a similar pathway is playing a role in prostate cancer, especially HRPC and bone metastatic disease. To test our hypothesis, we will investigate whether treatment of prostate cancer cells (LNCaP, AR +, responsive to androgen and C4-2B, AR +, non-responsive to androgen) in vitro and in vivo with DIM alone or in combination with Taxotere could show greater anti-tumor effects and whether this effect is mechanistically associated with inactivation of survivin signaling. To test our hypothesis, we will employ several techniques such as MTT, ELISA, Western blot, EMSA, cDNA and siRNA transfection including an animal study. The data obtained from our experiments will provide new mechanistic insight for discovering novel approaches for the treatment of HRPC and bone metastatic disease in the future.