Abstract
Metformin is a biguanide drug that is widely used in the treatment of diabetes. Epidemiological studies have indicated that metformin exhibits anti-cancer activity. However, the molecular mechanisms underlying this activity currently remain unclear. We hypothesized that metformin is cytotoxic in a tumor-specific environment such as glucose deprivation and/or low oxygen (O2) tension. We herein demonstrated that metformin was highly cytotoxic under glucose-depleted, but not hypoxic (2% O2) conditions. In order to elucidate the underlying mechanisms of this selective cytotoxicity, we treated exposed DNA repair-deficient chicken DT40 cells with metformin under glucose-depleted conditions and measured cellular sensitivity. Under glucose-depleted conditions, metformin specifically killed fancc and fancl cells that were deficient in FANCC and FANCL proteins, respectively, which are involved in DNA interstrand cross-link repair. An analysis of chromosomal aberrations in mitotic chromosome spreads revealed that a clinically relevant concentration of metformin induced DNA double-strand breaks (DSBs) in fancc and fancl cells under glucose-depleted conditions. In summary, metformin induced DNA damage under glucose-depleted conditions and selectively killed cells. This metformin-mediated selective toxicity may suppress the growth of malignant tumors that are intrinsically deprived of glucose.
Highlights
Metformin (1, 1-dimetyhlbiganide) is a biguanide drug that is used in the treatment of type II diabetes
In order to investigate whether metformin exerts cytotoxicity under glucose-depleted and/or low oxygen tension (2% O2) conditions, we measured the cellular sensitivity of wild-type DT40 cells to metformin
Metformin was highly cytotoxic under glucose-depleted, but not hypoxic conditions (Fig 1A). This result is consistent with previous findings showing the selective cytotoxicity of metformin when combined with the hypoglycemia-mimicking agent 2-deoxy-D-glucose [5,14]
Summary
Metformin (1, 1-dimetyhlbiganide) is a biguanide drug that is used in the treatment of type II diabetes. Metformin primarily acts in the liver to inhibit gluconeogenesis by reducing hyperglycemia and associated elevations in circulating insulin [1,2,3]. It is potentially beneficial for cancer prevention. Cytotoxicity of the anti-diabetic drug, metformin, in chicken DT40 cells the use of metformin and improved cancer-related mortality. Diabetic patients treated with metformin displayed a 31% lower overall relative risk of cancer and cancer-related mortality than those treated with other therapeutics [4]. Metformin has been shown to exhibit selective cytotoxicity during glucose deprivation [5]
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