Disease protection by DNA damage responses induced by anthracyclines

We have identified the anthracycline family of chemotherapeutic drugs (epirubicin, doxorubicin and daunorubicin) as potent antagonists of inflammatory cytokine production that are able to confer strong protection in a mouse model of severe sepsis. We also showed that Ataxia Telangiectasia Mutated (ATM)-dependent events are required for the extended survival, thus implicating the DNA damage response (DDR) in disease protection. The anti-cancer activity of anthracyclines is not fully understood, but it is known that these drugs inhibit type II topoisomerases and induce oxidative damage in the DNA as a consequence of the reactive oxygen species generated by their intracellular metabolism. Here we test the capacity of different anthracyclines to generate DNA damage in immune-responsive cells both directly, as assayed by comet assays, and by quantifying histone H2AX phosphorylation levels. We conclude that whereas the activation of DDR components is an intrinsic aspect of disease protection, cytokine up-regulation by anthracyclines is independent of DNA damage, as well as the regulation of a series of critical pro-inflammatory mediators. Importantly, the anthracycline-mediated effects on the expression of the inflammatory program are also observed in ATM-/- mice.