期刊
BREAST CANCER-BASIC AND CLINICAL RESEARCH
卷 8, 期 -, 页码 39-49出版社
SAGE PUBLICATIONS LTD
DOI: 10.4137/BCBCR.S13693
关键词
radiosensibility; Akt; DNA repair protraction; apoptosis; hypoxia; autophagy
类别
资金
- interdisciplinary Centre of Clinical research (iZKF) of the University of Wurzburg
- German Research Foundation (DFG)
- University of Wuerzburg
In the present study, we assessed, if the novel dual phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin ( mTOR) inhibitor NVP-BEZ235 radiosensitizes triple negative (TN) MDA-MB-231 and estrogen receptor ( ER) positive MCF-7 cells to ionizing radiation under various oxygen conditions, simulating different microenvironments as occurring in the majority of breast cancers (BCs). Irradiation (IR) of BC cells cultivated in hypoxic conditions revealed increased radioresistance compared to normoxic controls. Treatment with NVP-BEZ235 completely circumvented this hypoxiainduced effects and radiosensitized normoxic, reoxygenated, and hypoxic cells to similar extents. Furthermore, NVP-BEZ235 treatment suppressed HIF-1 alpha expression and PI3K/mTOR signaling, induced autophagy, and caused protracted DNA damage repair in both cell lines in all tested oxygen conditions. Moreover, after incubation with NVP-BEZ235, MCF-7 cells revealed depletion of phospho-AKT and considerable signs of apoptosis, which were significantly enhanced by radiation. Our findings clearly demonstrate that NVP-BEZ235 has a clinical relevant potential as a radiosensitizer in BC treatment.
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