1. Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma.
- Author
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Gil del Alcazar CR, Hardebeck MC, Mukherjee B, Tomimatsu N, Gao X, Yan J, Xie XJ, Bachoo R, Li L, Habib AA, and Burma S
- Subjects
- Animals, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Ataxia Telangiectasia Mutated Proteins metabolism, Blood-Brain Barrier metabolism, Catalytic Domain, Cell Line, Tumor, DNA-Activated Protein Kinase antagonists & inhibitors, DNA-Activated Protein Kinase chemistry, DNA-Activated Protein Kinase metabolism, Dacarbazine analogs & derivatives, Dacarbazine pharmacology, Disease Models, Animal, Glioblastoma drug therapy, Glioblastoma mortality, Glioblastoma pathology, Glioblastoma radiotherapy, Humans, Mice, Mice, Transgenic, Protein Interaction Domains and Motifs drug effects, Temozolomide, DNA Breaks, Double-Stranded drug effects, DNA Repair drug effects, Glioblastoma genetics, Glioblastoma metabolism, Imidazoles pharmacology, Phosphoinositide-3 Kinase Inhibitors, Quinolines pharmacology, Radiation-Sensitizing Agents pharmacology, TOR Serine-Threonine Kinases antagonists & inhibitors
- Abstract
Purpose: Inhibitors of the DNA damage response (DDR) have great potential for radiosensitization of numerous cancers, including glioblastomas, which are extremely radio- and chemoresistant brain tumors. Currently, there are no DNA double-strand break (DSB) repair inhibitors that have been successful in treating glioblastoma. Our laboratory previously demonstrated that the dual phosphoinositide 3-kinase/mTOR inhibitor NVP-BEZ235 can potently inhibit the two central DDR kinases, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia-telangiectasia mutated (ATM), in vitro. Here, we tested whether NVP-BEZ235 could also inhibit ATM and DNA-PKcs in tumors in vivo and assessed its potential as a radio- and chemosensitizer in preclinical mouse glioblastoma models., Experimental Design: The radiosensitizing effect of NVP-BEZ235 was tested by following tumor growth in subcutaneous and orthotopic glioblastoma models. Tumors were generated using the radioresistant U87-vIII glioma cell line and GBM9 neurospheres in nude mice. These tumors were then treated with ionizing radiation and/or NVP-BEZ235 and analyzed for DNA-PKcs and ATM activation, DSB repair inhibition, and attenuation of growth., Results: NVP-BEZ235 potently inhibited both DNA-PKcs and ATM kinases and attenuated the repair of ionizing radiation-induced DNA damage in tumors. This resulted in striking tumor radiosensitization, which extended the survival of brain tumor-bearing mice. Notably, tumors displayed a higher DSB-load when compared with normal brain tissue. NVP-BEZ235 also sensitized a subset of subcutaneous tumors to temozolomide, a drug routinely used concurrently with ionizing radiation for the treatment of glioblastoma., Conclusions: These results demonstrate that it may be possible to significantly improve glioblastoma therapy by combining ionizing radiation with potent and bioavailable DNA repair inhibitors such as NVP-BEZ235., (©2013 AACR)
- Published
- 2014
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