Abstract 2931: Zerumbone, a phytochemical from asian ginger inhibits JAK/STAT pathway, growth, apoptosis and increase taxol sensitivity of hormone refractory prostate cancer cells

Abstract

Abstract Objectives: Prostate cancer (PCa) is the most common cancer incidence and the second cancer death in U.S. men. In 2010, an estimated 217,730 new cases of PCa will be diagnosed, and 32,050 people will die from the disease in USA alone. IL-6 is strongly associated with malignant phenotype of PCa. IL-6 potently activates signal transducers and activators of transcription 3 (STAT3), a member of the family of latent cytoplasmic transcription factors that transmit signals from the cell membrane to the nucleus. STAT3 activation is known to promote tumor cell proliferation, survival, angiogenesis, and metastasis in vivo. In PCa, IL-6 strongly promotes mitogenic and angiogenic signaling through phosphorylation of Jak2 and then STAT3. Zerumbone, a relatively new anticancer component isolated from Zingiber zerumbet Smith has not been previously evaluated for prostate cancer. AIM: 1. Determine the activity and mechanism of zerumbone on hormone refractory prostate cancer cells. 2. Evaluate the combined effect of taxol (paclitaxel) with zerumbone in killing hormone-refractory prostate cancer cells. Methods and Results: The apoptosis and cytotoxic effect of zerumbone were determined by PARP cleavage (western blot) and MTS assay in DU145 cells. Zerumbone induced cytotoxicity with IC50 = 24 µM and significant PARP cleavage. Zerumbone (25 μM) potently inhibited constitutively activated Jak2/STAT3 phosphorylation and IL-6-stimulated STAT3 phosphorylation in DU145 cells as determined by western blots. Zerumbone (25 μM) also blocked expression of STAT3 dependent antiapoptotic proteins Bcl-xL. Interestingly, zerumbone even at a higher dose like 50uM has no effect on p65 subunit phosphorylation of NFkB and MAP kinase phosphorylation indicating a relative specificity. Next, we determined the combined effect of zerumbone and taxol in DU145 cells. Zerumbone as low as 10µM (4% cytotoxicity) synergistically increased cytotoxicity of taxol (5 nM, 7% cytotoxicity) to 25% cytotoxicity when combined. Zerumbone (10µM) also decreased IC50 of taxol from 12 nM to 7 nM. Conclusion: We showed that zerumbone is a potential therapeutic agent in prostate cancer by effectively blocking Jak2/STAT3-mediated signaling pathways and in addition, zerumbone combining with taxol based cytotoxic therapies may offer encouraging strategies for combating hormone-refractory prostate cancers. 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 2931. doi:10.1158/1538-7445.AM2011-2931