Disruption of Hif-1α enhances cytotoxic effects of metformin in murine squamous cell carcinoma. (2nd January 2018)

• Record Type: Journal Article
• Authors: Sanada, Yu; Sasanuma, Hiroyuki; Takeda, Shunichi; Tano, Keizo; Masunaga, Shin-ichiro
• Is Part Of: International journal of radiation biology. Volume 94:Number 1(2018)
• Page Start: 88
• Page End: 96
• Publication Date: 2018-01-02
• Subjects: Metformin -- glucose deprivation -- hypoxia -- tumor microenvironment -- radiosensitivity; Radiation -- Physiological effect -- Periodicals; Radiobiology -- Periodicals; 571.45
• DOI: 10.1080/09553002.2018.1409443
• Languages: English
• ISSNs: 0955-3002

Abstract

Abstract: Purpose: In the present study, we investigated whether the disruption of the Hif-1α gene affects the sensitivity of SCC VII cells to metformin and also if metformin functions as a radiosensitizer using murine squamous cell carcinoma (SCC VII) cells. Materials and methods: Cultured SCC VII and SCC VII Hif-1α-deficient cells were incubated with metformin under glucose-free and/or hypoxia-mimetic conditions and cell viabilities were measured. Tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating cells. Tumor-bearing mice were then subjected to γ-ray irradiation after the metformin treatment. Immediately after irradiation, cells were isolated from some tumors and incubated with a cytokinesis blocker. The responses of quiescent and total (= proliferating + quiescent) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. Results: The disruption of Hif-1α increased the sensitivity of SCC VII cells to metformin in glucose-free medium. Metformin-induced decreases in the percentage of dead cells in the presence of CoCl2 were partially reduced when Hif-1α was disrupted. In vivo, metformin increased the radiosensitivity of SCC VII Hif-1α-deficient cells. Conclusion: The combination of disruption of Hif-1α and metformin effectively enhanced the radiosensitivity of SCC VII cells.