Snake venoms promote stress‐induced senescence in human fibroblasts

Snake venoms are widely studied in terms of their systemic toxicity and proteolytic, hemotoxic, neurotoxic, and cytotoxic activities. However, little is known about snake‐venom‐mediated effects when used at low, noncytotoxic concentrations. In the current study, two human fibroblast cell lines of different origin, namely WI‐38 fetal lung fibroblasts and BJ foreskin fibroblasts were used to investigate snake‐venom‐induced adaptive response at a relatively noncytotoxic concentration (0.01 µg/ml). The venoms of Indochinese spitting cobra ( Naja siamensis), western green mamba ( Dendroaspis viridis), forest cobra ( Naja melanoleuca), and southern copperhead ( Agkistrodon contortrix) were considered. Snake venoms promoted FOXO3a‐mediated oxidative stress response and to a lesser extent DNA damage response, which lead to changes in cell cycle regulators both at messenger RNA and protein levels, limited cell proliferation and migration, and induced cellular senescence. Taken together, we have shown for the first time that selected snake venoms may also exert adverse effects when used at relatively noncytotoxic concentrations. In the current study, we show that subtoxic concentrations of selected snake venoms promote FOXO3a‐mediated oxidative stress response and to a lesser extent DNA damage response that results in changes in the levels of cell cycle regulators leading to cell cycle arrest and stress‐induced premature senescence (SIPS) in human fibroblasts in vitro.