PV QA 1 - Poster Viewing Q&A 1
Purpose/Objective(s): Hepatocyte growth factor receptor (c-Met) is overexpressed in cancer and plays a crucial role in inhibition of apoptosis. The small-molecule c-Met inhibitor BPI-9016M can enhance the cytotoxicity of various DNA-damaging agents and promote apoptosis. Here, we evaluated the radiosensitizing potential of BPI-9016M in Eca109 human esophageal squamous cell carcinoma (ESCC) cells.
Materials/Methods: Cell viability was determined using the CCK-8 assay. The radiosensitizing effect of BPI-9016M was evaluated using the clonogenic survival assay and a murine tumor xenograft model. Apoptosis was determined by flow cytometric analysis and TUNEL staining. Apoptosis-related proteins were detected by western blot analysis. Radiation-induced DNA double strand break and homologous recombination repair were probed by assessing activation of the ATR-Chk1/ATM-Chk2 pathways.
Results: BPI-9016M induced a radiosensitizing effect in Eca109 cells and reduced clonogenic survival in vitro. Combination of BPI-9016M with irradiation delayed the growth of ESCC tumor xenografts more significantly that either treatment alone (P < 0.05). The radiosensitizing effects of BPI-9016M were due to increased apoptosis, as confirmed by upregulation of cleaved-caspase 3 and 9, downregulation of mutant P53 and Bcl-2, decreased phosphorylation of ATR and ATM, and inhibition of γ-H2AX accumulation both in vitro and in vivo.
Conclusion: These findings suggest BPI-9016M exerts a radiosensitizing effect to enhance apoptosis by inhibiting homologous recombination DNA repair in irradiated ESCC cells.
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