US EPA

4453282 

Journal Article 

Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells 

Kadoda, K; Moriwaki, T; Tsuda, M; Sasanuma, H; Ishiai, M; Takata, M; Ide, H; Masunaga, SI; Takeda, S; Tano, K 

2017 

1 

PLoS ONE
EISSN: 1932-6203 

12 

9 

e0185141 

English 

28926637 

10.1371/journal.pone.0185141 

WOS:000411166600074 

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.