High-dose metformin induces a low-glucose dependent genotoxic stress. (July 2022)

• Record Type: Journal Article
• Authors: Lyu, Ting; Zhou, Hongyuan; Wang, Yihui; Jiang, Minyan; Tao, Qian; Chen, Juanlin; Guo, Yitong; Zhang, Qiuping; Wang, Xu; Guo, Xihan
• Is Part Of: Food and chemical toxicology. Volume 165(2022)
• Publication Date: 2022-07
• Subjects: Metformin -- Chromosomal instability -- Glucose -- Genotoxicity -- Anti-genotoxicity; MN mcronuclei -- SAC spindle assembly checkpoint -- T2D type 2 diabetes -- AMPK adenosine monophosphate (AMP)–activated protein kinase -- HUVECs human umbilical vein endothelial cells -- CBMN cytokinesis-blocked micronuclei -- RT-qPCR real-time quantitative PCR -- NPB nucleoplasmic bridges -- NB nuclear buds -- BNCs binucleated cells -- SEM standard error of the mean; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2022.113129
• Languages: English
• ISSNs: 0278-6915

Abstract

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. Graphical abstract: Image 1 Highlights: Metformin elicits short- and long-term effects to inhibit the growth of cancer cells. Metformin causes significant genotoxic stress in cancer cells. Metformin de-regulates the expression of core SAC genes. Metformin is genotoxic to non-cancer cells. The genotoxic and anti-genotoxic effects of metformin depend on glucose availability.