Genome protective effect of metformin as revealed by reduced level of constitutive DNA damage signaling

Abstract

We have shown before that constitutive DNA damage signaling represented by H2AX-Ser139 phosphorylation and ATM activation in untreated normal and tumor cells is a reporter of the persistent DNA replication stress induced by endogenous oxidants, the by-products of aerobic respiration. In the present study we observed that exposure of normal mitogenically stimulated lymphocytes or tumor cell lines A549, TK6 and A431 to metformin, the specific activator of 5'AMP-activated protein kinase (AMPK) and an inhibitor of mTOR signaling, resulted in attenuation of constitutive H2AX phosphorylation and ATM activation. The effects were metformin-concentration dependent and seen even at the pharmacologically pertinent 0.1 mM drug concentration. The data also show that intracellular levels of endogenous reactive oxidants able to oxidize 2',7'-dihydro-dichlorofluorescein diacetate was reduced in metformin-treated cells. Since persistent constitutive DNA replication stress, particularly when paralleled by mTOR signaling, is considered to be the major cause of aging, the present findings are consistent with the notion that metformin, by reducing both DNA replication stress and mTOR-signaling, slows down aging and/or cell senescence processes.

Enhanced cytotoxic effect of low doses of metformin combined with ionizing radiation on hepatoma cells via ATP deprivation and inhibition of DNA repair

“…It is striking to observe a minor increase in the expression of γ-H2AX after 1 h of treatment with 10 µM metformin but not after 24 h. Our findings concur with the recent observation of Halicka et al (34), who reported that metformin treatment for 24-48 h decreased rather than increased the level of the constitutive expression of γ-H2AX, possibly by decreasing oxidative stress (34). Possibly the same mechanism is involved in the reduction of γ-H2AX expression after treatment with metformin for 1 h as compared for 24 h.…”

Spatiotemporal recruitment of human DNA polymerase delta to sites of UV damage

“…However, given that p12 levels respond to DNA damage, this could be reasonably explained since the cells are constantly responding to endogenous sources of DNA damage, such as deamination and oxidative damage. 58,59 It should be noted, however, that whereas the S-phase cells are characterized by minimal expression of p12 subunit, distinctly below the minimal level of that of G 1 and G 2 M cells, the expression of p50 is also somewhat lower during S phase, although not to such an extent as p12 (Fig. 5 and Table 1).…”

Mitochondrial Metabolic Reprogramming Induced by Calorie Restriction

“…It has been proposed that metformin compromises ATP production in the mitochondria. The mechanism of action would be based in a mild inhibition of the mitochondrial complex I. Interestingly, although the increase of oxidative damage due to the inhibition of mitochondrial complexes is a well-established fact, metformin seems to reduce ROS generation and oxidative damage accumulation (1,37,40,84). Supporting these findings, an increase of the expression of antioxidant proteins has been reported in cells and animals treated with metformin (45,72).…”