RRC ID 51297
Author Kadoda K, Moriwaki T, Tsuda M, Sasanuma H, Ishiai M, Takata M, Ide H, Masunaga SI, Takeda S, Tano K.
Title Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells.
Journal PLoS ONE
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.
Volume 12(9)
Pages e0185141
Published 2017
DOI 10.1371/journal.pone.0185141
PII PONE-D-17-20406
PMID 28926637
PMC PMC5605006
MeSH Animals Cell Line Cell Survival / drug effects Chickens Chromosome Aberrations / drug effects DNA Breaks, Double-Stranded / drug effects* DNA Repair / drug effects Glucose / chemistry Hypoglycemic Agents / toxicity* Metformin / toxicity* Oxygen / chemistry Oxygen / metabolism
IF 2.766
Resource
Prokaryotes E. coli