Abstract
The present study addressed whether the combination of metformin and ionizing radiation (IR) would show enhanced antitumor effects in radioresistant p53-deficient colorectal cancer cells, focusing on repair pathways for IR-induced DNA damage. Metformin caused a higher reduction in clonogenic survival as well as greater radiosensitization and inhibition of tumor growth of p53-/- than of p53+/+ colorectal cancer cells and xenografts. Metformin combined with IR induced accumulation of tumor cells in the G2/M phase and delayed the repair of IR-induced DNA damage. In addition, this combination significantly decreased levels of p53-related homologous recombination (HR) repair compared with IR alone, especially in p53-/- colorectal cancer cells and tumors. In conclusion, metformin enhanced radiosensitivity by inducing G2/M arrest and reducing the expression of DNA repair proteins even in radioresistant HCT116 p53-/- colorectal cancer cells and tumors. Our study provides a scientific rationale for the clinical use of metformin as a radiosensitizer in patients with p53-deficient colorectal tumors, which are often resistant to radiotherapy.
Highlights
Radiotherapy is widely used for the definitive and adjuvant treatment of numerous cancers [1]
The combination of metformin and ionizing radiation (IR) markedly reduced clonogenic survival compared with IR alone in HCT116 p53-/- (p < 0.01), but not p53+/+ cells, suggesting that radiosensitization was higher in HCT116 p53-/- than in p53+/+ cells
To investigate whether metformin affected DNA repair pathways in vitro, we examined the expression of p53-related homologous recombination (HR) repair proteins including the meiotic recombination 11 (MRE11)-Rad50-p95/Nijmegen breakage syndrome protein 1 (NBS1) complex, BRCA1, BRCA2, Rad51, Rad52, and excision repair cross-complementation group 1 (ERCC1) in HCT116 p53+/+ and p53-/- cells using immunoblotting
Summary
Radiotherapy is widely used for the definitive and adjuvant treatment of numerous cancers [1]. Resistance to radiotherapy remains an important concern [2]. Various factors including p53 mutation [3], overexpression of DNA repair proteins [4,5,6], and tumor microenvironment [7, 8] have been proposed to play roles in radioresistance. P53 mutation is regarded as good candidate for radioresistance markers [9]. The tumor suppressor factor p53, which plays a central role in the cellular responses to DNA damage, promotes cell survival (cell-cycle arrest, DNA repair, and autophagy) at low levels of DNA damage while it induces cell death at high levels.
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