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A4649 - TAS-116, a Novel Heat Shock Protein 90 Inhibitor, Enhances Radiosensitivity of Lung Cancer Cells
Author Block: B. Chang, M. Park, J. Yoo, S. Lee, J. Lee, M. Kang, S. Han; Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea, Republic of.
Background: Heat shock protein 90 (HSP 90) is a molecular chaperone which is critical in intracellular protein homeostasis by involving protein maturation and stability. TAS-116, a novel HSP90 inhibitor with lower adverse effects than other HSP 90 inhibitors showed potential role as a chemosensitizer in a variety of cancers both in vitro and in vitro. However, there is no data on the role of TAS-116 combined with radiotherapy in lung cancer. Thus, we investigated radiosensitizing effects of TAS-116 in lung cancer cells. Methods: Various concentrations of TAS-116, either alone or in combination with ionizing radiation (from 0 to 4 Gy), were applied to lung cancer cells (A549, H460 and DMS273 cells). We evaluated its radiosensitizing activity of TAS-116 by colony forming assay, RAD51 foci formation for double-strand breaks (DSB) and flow cytometric analysis. Results: TAS-116 reduced cell viability and suppressed HSP 90 expression in lung cancer cell lines dose-dependently similar to other Hsp90 inhibitors. TAS-116 delayed the repair of DNA by reducing the expression of proteins that mediate repair of DSB. TAS-116 also decreased expression of the cdc25 cell-cycle progression marker, markedly increasing G2-M arrest. Combined treatment with ionizing radiation and TAS-116 showed marked delay in cell proliferation compared with either individual treatment. Conclusions: These results demonstrate that TAS-116 sensitizes human lung cancer cells to ionizing radiation by inhibiting DSB repair pathways and inducing cell-cycle arrest.