Radiosensitization by inhibition of Hsp90 and microenvironmental factors

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Activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway is known to induce tumor radioresistance. In the current studies, we examined the ability of 17-Allylamino-17-demethoxygeldanamycin (17AAG), which decreases the levels of Hsp90 client proteins including components of the PI3K-Akt pathway, to sensitize radioresistant human squamous cell carcinoma cells to X-irradiation. 17AAG (0.2 μM) enhanced the radiosensitivity more effectively in radioresistant SQ20B and SCC 13 cells than in radiosensitive SCC61 cells. However, in all three cell lines, 17AAG increased radiation-induced apoptosis by reducing the expression of the epidermal growth factor receptor and ErbB-2 and inhibiting the phosphorylation of Akt. Furthermore, 17AAG (1 μM) sensitized SQ20B spheroids to radiation, and inhibition of Akt activation by 17AAG increased radiation-induced apoptosis in spheroids. The findings suggest that 17AAG effectively sensitizes radioresistant cells to radiation by inhibiting the PI3K-Akt pathway.We also tested the effect of a combination of GA and radiation on cell survival, PI3K/Akt-related proteins and apoptosis induction in human tumor and normal cells. GA sensitized tumour cells in preference to normal cells to radiation. In addition, a combination of radiation and GA abolished Akt activities and strongly enhanced the induction of apoptosis in tumour cells which depend on Akt protein activities for cell survival. The present data support the hypothesis that GA sensitizes tumour cells by modulating the balance among mitogenic, antiproliferative and apoptotic pathways. Thus, targeting Hsp90 in tumour cells may lead to the development of new radiosensitizing strategies in radiotherapy.