Abstract 5659: Down-regulation of hTERT sensitizes chemotherapeutic effects of docetaxel in human prostate cancer cells via suppression of PIM-1 oncogene

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Taxanes comprise some of the most widely used cancer chemotherapeutic agents for various cancers. Docetaxel is an effective first-line treatment for hormone-refractory prostate cancer. However, despite the recently demonstrated survival benefits of docetaxel-based chemotherapy, most patients will move from response to progression within 6 months. Moreover, effective concentrations of docetaxel have side effects including localized erythema of the extremities with edema followed by desquamation, severe neuropathy, fatigue, and weakness which can have debilitating effects in patients with prostate cancer. One reason for disease progression is the up-regulation of PIM-1 expression following docetaxel treatment of prostate cancer cells. PIM-1 is a serine-threonine kinase that promotes survival by inhibiting the activity of apoptotic proteins. In a recent study, we observed that a telomerase suppressing small molecule MST-312, and hTERT siRNA down-regulated PIM-1 protein level in prostate cancer cells. These results prompted us to investigate whether combination of docetaxel with inhibition of telomerase by MST-312 or TERT siRNA would have synergistic effects on prostate cancer cell growth and induce death. Treatment of PC3 cells with 1 nM of docetaxel for 3 days substantially promoted the viability of cells compared to the control, with a 27% increase in cell number. This increase was associated with the up-regulation of PIM-1. Treatment of telomerase inhibitory concentration (2 μM) of MST-312 over 3 days resulted in a 51% decrease in cell viability relative to the 1 nM docetaxel treated groups, associated with a decrease in PIM-1 protein levels. More interestingly, treatment of 2 μM MST-312 with 1 nM docetaxel for 3 days resulted in 72% reduction in cell viability compared to docetaxel alone and 43% reduction in cell viability compared to MST-312 alone. This combined treatment also resulted in lower levels of PIM-1 activity than MST-312 or docetaxel treatment alone. These results suggest that there is synergy between the combination of telomerase inhibitor MST-312 with docetaxel in the treatment of metastatic prostate cancer. This can be explained by the down-regulation of PIM-1 kinase that promotes resistance to docetaxel treatment. These findings suggest potential clinical benefit by the combined use of docetaxel and telomerase inhibitors for prostate cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5659.