Abstract
Abstract Purpose: Most drug resistance cancer cells have resisted to radiation therapy. In this study, we hypothesized that a dual inhibitor of PI3-kinase/ the downstream mammalian target of rapamycin (mTOR), BEZ235, could potentially enhance radiosensitization in cisplatin-selected non- small cell lung cancer stem cells. Methods: Clonogenic assay was used to determine radiosensitivity. Stem cell marker was detected with CD133 antibody. P-AKT, P-mTOR and P-S6R were detected by Western Blotting. Cell cycle was performed using flow cytometry. Autophagy was determined by punctuate localization of GFP-LC3 fusion protein, which observed under a confocal fluorescence microscope in vitro. Results: Basal CD133 which is a marker of stem cell, P-Akt, p-mTOR and P-S6R proteins were enhanced in cisplatin-selected non- small cell lung cancer stem cells (CSNSCLCSTC) when compared to parental non-small cell lung cancer (H460) cells. Cisplatin-selected non- small cell lung cancer stem cells mediate less radiation sensitivity when compared with parental cells in clonogenic assay(DER=0.82, p=0.02). However BEZ235 obviously enhanced sensitivity of cisplatin-selected non- small cell lung cancer stem cells to radiation (DER=1.2, p=0.01). Therefore, this enhanced radiosensitization was associated with a downregulation of PI3-kinase/mTOR signaling pathway and an increase in characteristic punctuate localization of GFP-LC3 as a marker for autophagy, suggesting that G2/M inhibition and autophagy were induced simultaneously. Conclusions: These findings may be utilized as a novel strategy to enhance radiation therapy in drug-selected non-small cell lung cancer stem cells showing radioresistance. 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 3326.
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