Abstract 1218: SMAC modulates gemcitabine-induced apoptosis in head and neck cancer cells

Abstract

Abstract Apoptosis induction is an important anti-tumor mechanism of many conventional chemotherapeutic agents. Biochemical data indicate that SMAC promotes caspase activation by antagonizing IAPs. However, SMAC-knockout mice do not exhibit obvious apoptotic deficiencies in response to a wide range of stimuli. Work for us and others demonstrate that SMAC plays an essential role in apoptosis induced by Nonsteroidal Anti-inflammatory Drug (NSAID), TRAIL or BH3 only proteins in colon cancer cells. In this study we documented a critical role of SMAC in mediating apoptosis induced by chemotherapeutic agent gemcitabine in head and neck squamous cell carcinoma (HNSCC) cells. Using RNA interference, we found that that SMAC mediates gemcitabine-induced apoptosis through the intrinsic/mitochondrial pathway. SMAC Knockdown led to impairment in caspase-3 activation, mitochondrial membrane depolarization and release of cytochrome c. Small-molecule SMAC mimetics at nanomolar concentrations significantly sensitized HNSCC cells to gemcitabine-induced apoptosis, and overcame gemcitabine resistance in SMAC-knockdown cells by restoring caspase-3 activation and cytochrome c release. Furthermore, in xenograft models, SMAC knockdown significantly blocked the therapeutic responses of HNSCC tumors to gemcitabine by inhibiting apoptosis, while SMAC overexpression dramatically enhanced that. Together, these results suggest that SMAC mediates apoptosis in cancer cells, and provide a strong rationale for combining SMAC mimetics with other anticancer agents to treat apoptosis-resistant tumors. 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 1218.