Radiosensitization of the PI3K inhibitor HS-173 through reduction of DNA damage repair in pancreatic cancer.

In this study, we investigated whether the novel PI3K inhibitor HS-173 could attenuate radiation-induced up-regulation of DNA damage repair processes and assessed its efficacy as a radio- and chemo-sensitizer. Radiosensitizing effects of HS-173 were tested in human pancreatic cells using clonogenic survival and growth assays. Mechanisms underlying the effects of HS-173 and radiation were determined by assessing cell cycle and DNA damage- repair pathway components, including ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). The in vivo efficacy of HS-173 in cancer radiotherapy was evaluated using a human tumor xenograft model. HS-173 significantly increased the sensitivity of pancreatic cancer cells to radiation, an effect that was associated with G2/M cell cycle arrest. HS-173 also significantly attenuated DNA damage repair by potently inhibiting ATM and DNA-PKcs, the two major kinases that respond to radiation-induced DNA double-strand breaks (DSBs), resulting in sustained DNA damage. Moreover, the combination of HS-173 and radiation delayed tumor growth and impaired DNA repair in a pancreatic cancer xenograft model, reflecting enhanced radiosensitization. These results showed that HS-173 significantly improved radiotherapy by inhibiting the DNA damage-repair pathway in pancreatic cancer. We therefore suggest that HS-173 may be an effective radiosensitizer for pancreatic cancer. PMID: 29348875 [PubMed]
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research