RRC ID |
51297
|
著者 |
Kadoda K, Moriwaki T, Tsuda M, Sasanuma H, Ishiai M, Takata M, Ide H, Masunaga SI, Takeda S, Tano K.
|
タイトル |
Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells.
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ジャーナル |
PLoS One
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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.
|
巻・号 |
12(9)
|
ページ |
e0185141
|
公開日 |
2017-9-19
|
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 |
2.74
|
引用数 |
2
|
リソース情報 |
原核生物(大腸菌) |
|