High-dose metformin induces a low-glucose dependent genotoxic stress
Abstract
Epidemiological studies have demonstrated that metformin (a cornerstone of diabetes treatment) has anticancer activity, but the underlying mechanism remains elusive. We aimed to investigate whether metformin elicits anticancer activity via increasing genotoxic stress, a state of increased genome damage that becomes tumor-suppressing if it goes beyond an intolerable threshold. We found that metformin (1-16 mM) suppressed proliferation and colony formation in a panel of cancer cell lines (HeLa, A375, A549 and QGY). Metformin induced a dose-dependent increase of genotoxic stress (including micronucleus, nucleoplasmic bridge and nuclear bud) and the increase of genotoxic stress correlated well with metformin's anticancer potential. Metformin deregulated the expression of BUBR1 and MAD2, two core genes of spindle assembly checkpoint (SAC) that surveillances chromosome segregation. Metformin had weakened antiproliferative effect and a corresponding attenuated genotoxic effect in HeLa cells cultured in high glucose (16 mg/ml). Meanwhile, metformin significantly increased genotoxicity in non-cancer cells (NCM460 and HUVECs). Metformin became non-genotoxic to HUVECs in high-glucose (8 and 16 mg/ml) conditions and reduced the genotoxicity of high glucose. Overall, these results infer a new mechanism of high-dose metformin, whereby low-glucose dependent genotoxic stress derived from SAC dysfunction might mediate some of the anticancer effect of this drug.
Read the paper
Related studies
- Metformin as an adjuvant in breast cancer treatment
- Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
- Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice
- Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines
- Protein Interaction Network for Identifying Vascular Response of Metformin (Oral Antidiabetic)
- Preventing Long COVID With Metformin
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.