The MTH1 inhibitor TH287 sensitized Castration-Resistant Prostate Cancer cells to ionizing radiation therapy

OBJECTIVES: To determine whether the MutT Homolog 1 (MTH1) inhibition could increase the sensitivity of Castration-Resistant Prostate Cancer (CRPC) cells to Radiotherapy (RT), as well as to determine the appropriate application time of the MTH1 inhibitor and RT to achieve optimal radiosensitizing effects. METHODS: PC-3 and DU-145 cells were selected as the model cell lines for CRPC. After 24 h of incubation, the cells were treated with various doses of the MTH1 inhibitor TH287 for 72 h, during which they were subjected to Ionizing Radiation (IR) treatment at 12, 24, and 48 h after the initial drug treatment. Cell survival was evaluated through the Cell Counting Kit 8 (CCK-8) assay. Apoptotic induction and cell cycle progression were evaluated through Western Blotting (WB) and flow cytometry analyses. RESULTS: The CCK-8 assay revealed that the TH287 + IR combination therapy significantly inhibited PC3 and DU145 cell survival, with the most potent effects observed in the combined IR administration at 12 h (P < 0.05). Furthermore, Annexin-V/PI (Propidium Iodide) dual staining revealed that the TH287 + IR combination treatment induced apoptotic tumor cell death more effectively than either treatment alone (P < 0.05). Moreover, WB analysis revealed that the TH287 + IR combination therapy significantly altered caspase-3 expression, indicating DNA damage induction and modulation of various cell cycle-related proteins. Moreover, flow cytometry analysis revealed that the TH287 + IR treatment caused significant G2/S-phase arrest in prostate cancer cells (P < 0.05). CONCLUSION: Overall, TH287 exhibited potent radiosensitization effects for CRPC treatment, effectively killing tumor cells when administered alongside IR at 12 h after the initial drug treatment.