Metformin inhibits the growth of nasopharyngeal carcinoma cells and sensitizes the cells to radiation via inhibition of the DNA damage repair pathway

Abstract

Nasopharyngeal carcinoma (NPC) is a leading cause of cancer-related mortality. Radiotherapy is one of the primary modalities for NPC treatment. However, in patients in the late stages of the disease, the local control rate and overall survival rate remain low. Therefore, it is urgent to identify new targets that can improve the outcome of radiotherapy in this neoplasm. In the present study, we investigated the effects of metformin on the radiosensitivity of NPC cells and explored the potential mechanisms. The radiosensitizing effects of metformin on NPC cells were measured by colony formation assay. Cell apoptosis was assessed by Hoechst 33342 staining analysis. DNA damage was detected by monitoring γ-H2AX foci with immunofluorescence. The changes in apotosis-related and DNA damage repair-related proteins were detected by western blotting. Our study demonstrated that metformin significantly reduced the cell viability, enhanced radiosensitivity and potentiated radiation-induced caspase-9/-3 cleavage in the NPC cells. In addition, metformin plus radiation significantly upregulated the expression of p-ATM, p-ATR, γ-H2AX and downregulated the expression of ATM, ATR, p95/NBS1, Rad50, DNA-PK, Ku70 and Ku80. Therefore, our results suggest that metformin possesses a strong radiosensitizing potential in NPC cells. This radiosensitizing effect was associated with inhibition of DNA double-strand break repair processes through HR repair and the NHEJ repair signaling pathway, thereby enhancing radiation-induced cell apoptosis. These findings imply that metformin is a potent radiation-sensitizing agent and may be a promising candidate for clinical evaluation as part of a combined regimen for the treatment of nasopharyngeal carcinoma.

Metformin enhances the radiosensitivity of human liver cancer cells to γ-rays and carbon ion beams

“…These results are consistent with those of previous reports that metformin potentiated radiation-induced caspase-9/-3 cleavage and PARP-dependent cell death in nasopharyngeal and breast cancer cells [29, 30]. These data may partially explain why carbon ion beams combined with metformin more effectively destroy HCC cells than γ-rays combined with metformin.…”

Metformin in combination with JS-K inhibits growth of renal cell carcinoma cells via reactive oxygen species activation and inducing DNA breaks

“…The increased cellular DNA damage might be caused by the excess ROS generation and result in subsequent apoptosis and suppression of proliferation in the RCC cells ACHN and A498. Furthermore, MET suppressed the growth of carcinoma cells by inhibiting the DNA damage repair pathway [37]. To assess the role of MET in regulating cellular DNA repair, we assessed the effect of MET on the expression of PCNA and Rad51, the two markers that serve crucial functions in DNA repair.…”

Astrocyte elevated gene-1 in relation to colorectal cancer development and radiotherapy response

“…The expression of p73, however, has been shown in cell line studies to increase shortly after genotoxic treatment like radiation, but does not sustain over several days and the protein expression of Rad50 did not alter upon DNA damage in several cell line models (206,(321)(322)(323). …”