ABT-737, A BH3 MIMETIC, LEADS TO RADIOSENSITIZATION OF HEAD AND NECK SQUAMOUS CELL CARCINOMA VIA INDUCTION OF INTRAMITOCHONDRIAL OXIDATIVE STRESS
Résumé
Head and neck squamous cell carcinomas (HNSCC), the sixth most common cancer worldwide, have an overall 5-year survival rate around 30% and this despite new therapeutic approaches including surgery, chemo-radiotherapy or targeted-therapies. Moreover, the classical therapy combining platinum-based chemotherapy and radiotherapy is associated with acute and chronic toxicities and a severely reduced quality of life. In order to significantly improve overall patient survival and reduce treatment toxicity, new drugs or combined treatments are urgently needed. The resistance of HNSCC cells to chemoradiotherapy is partly due to the over-expression of anti-apoptotic members of the Bcl-2 protein family, resulting in an inhibition of apoptosis in these cancer cells. In this context, Bcl-2 inhibition strategies have recently re-emerged as promising tools to specifically target these resistant cancer cells. ABT-737, a BH3-mimetic family member, binds and inhibits anti-apoptotic Bcl-xL, Bcl-2, and Bcl-w proteins but shows little affinity for Mcl-1 and Bcl2A1 (Osterdorf et al., 2005). Beside their role in the induction of the mitochondrial transition pore through the release of pro-apoptotic proteins Bax and Bak, Bcl-2 targeting strategies have been reported to act on the redox properties of Bcl-2 proteins. Thus Wilkins et al. (2012) recently demonstrated that Bcl-2 activates the 2-oxoglutarate carrier (OGC), the main carrier of glutathione (GSH) into mitochondria. GSH, the main nonenzymatic antioxidant, has to be imported from the cytosol in order to regulate the intramitochondrial redox balance. Our work demonstrates that a pre-treatment with ABT737 before irradiation can radio-sensitize HNSCC cell lines of graduate radiosensitivities and triggers apoptotic cell death. We show that the combined therapy triggers cell death through the generation of a major intra-mitochondrial oxidative stress. References: Oltersdorf et al. Nature (2005) 435:677 Wilkins et al. Free Radic Biol Med (2012) 52:410 This project was conducted under the framework of PRRH-ETOILE and LABEX PRIMES (ANR-11LABX-0063).