Abstract 3535: Diindolylmethane potentiates the effect of cisplatin in ovarian cancer cells by inhibiting STAT-3 and VEGF

Abstract

Abstract Ovarian cancer remains the second leading gynecological cancer in United States. It is usually detected in late stages with poor prognosis. Cisplatin is a chemotherapeutic drug currently used to treat patients with ovarian cancer. However, ovarian tumors develop resistance and cisplatin is associated with systemic toxicity. We previously reported that Diindolylmethane (DIM), a natural compound present in cruciferous vegetables inhibits the proliferation of ovarian cancer cells [Kandala and Srivastava, Mol. Pharmacol. 2010, 78, 297-309]. In this study, we evaluated the effect of DIM with cisplatin in ovarian cancer cells. Exposure of SKOV-3 cells to 50μM DIM for 24 hours followed by treatment with 10µM cisplatin resulted in about 70% reduction in the survival of cells as compared to 30% by cisplatin treatment alone. Western blot analyses indicate that combination (DIM + cisplatin) treatment block the activation of STAT-3 by inhibiting the phosphorylation at Tyr 705 and Ser 727 as compared to cisplatin or DIM treatment alone. The STAT-3 protein level was reduced by 90% by combination treatment. Mcl-1and survivin, which are regulated by STAT-3 were also down-regulated by combination treatment. Interestingly, survivin was up-regulated by cisplatin treatment but completely blocked by combination treatment. Increased apoptosis by combination treatment was evident by caspase-3 and PARP cleavage. In addition, we tested the effects of this combination treatment on ovarian tumor angiogenesis and metastatsis. The results of aortic ring assay suggested that the combination treatment completely suppressed the formation of microvessel sprouts. Furthermore, combination treatment blocked invasion of cells by approximately 50% as evaluated by Boyden's chamber. Combination of DIM and cisplatin suppressed VEGF secretion by 50% as compared to 20% by cisplatin treatment in SKOV-3 cells. Taken together, our results suggest that DIM potentiates the effect of cisplatin by blocking the activation of STAT-3 and inhibiting angiogenesis and metastasis. Further mechanistic and in vivo testing of this combination treatment is under progress. [Supported in part by R01 grants CA106953 and CA 129038 (to S.K.S) awarded by the National Cancer Institute]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3535. doi:10.1158/1538-7445.AM2011-3535