title: 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.
authors.affiliation: Cancer Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524000, P.R. China.
authors.forename: Haiwen
authors.initials: H
authors.lastname: Li
authors.affiliation: Cancer Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524000, P.R. China.
authors.forename: Xinggui
authors.initials: X
authors.lastname: Chen
authors.affiliation: Cancer Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524000, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Cancer Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524000, P.R. China.
authors.forename: Zhennan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Cancer Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524000, P.R. China.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Zuo
authors.affiliation: Cancer Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524000, P.R. China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Li
authors.affiliation: Cancer Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524000, P.R. China.
authors.forename: Donghong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Cancer Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524000, P.R. China.
authors.forename: Shengwen
authors.initials: S
authors.lastname: Hu
authors.affiliation: Cancer Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524000, P.R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Xiang
authors.affiliation: Cancer Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524000, P.R. China.
authors.forename: Zumin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Cancer Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524000, P.R. China.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Yu
mesh_terms: D017209:Apoptosis; D002277:Carcinoma; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: C468783:H2AX protein, human; D006657:Histones; D011838:Radiation-Sensitizing Agents; D008687:Metformin; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D045643:DNA Repair Enzymes