We found important new cues into the molecular mechanisms of disease tolerance induction by DNA damage responses. Our main results relate to the precise identification of the molecular mechanism by which anthracyclines specifically block the transcription of NFkB targets, when used at concentration below cytotoxic levels. In the course of this investigation, we also found that low levels of DNA damage promote survival against TNF-induced cell death, in an NFkB-independent manner. Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II poisoning and to eviction of histones from select sites in the genome. We discovered that the extensively used anthracyclines Doxorubicin, Daunorubicin and Epirubicin, decrease the transcription of nuclear factor kappa B (NF-κB)-dependent gene targets, but not interferon responsive genes. Using an NMR-based structural approach, we demonstrated that anthracyclines disturb the complexes formed between the NF-B subunit RelA and its DNA binding sites. The variant anthracyclines Aclarubicin, Doxorubicinone and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other anthracyclines but do not induce DNA damage, also suppressed inflammation, thus uncoupling DNA damage from the effects on inflammation. This has implications for anticancer therapy and for the development of novel anti-inflammatory drugs with limited side effects for life-threatening conditions such as sepsis. In addition to DNA damage, we explored the effects on the progress of a severe infection of protein synthesis inhibition in the mitochondria, which more that 50% of all classes of antibiotics in use cause. Several classes of antibiotics have long been known to have beneficial effects that cannot be explained strictly on the basis of their capacity to control the infectious agent. We discovered that tetracycline antibiotics, which target the mitoribosome, protected against sepsis, without affecting the pathogen load. Mechanistically, we found that mitochondrial inhibition of protein synthesis perturbed the electron transport chain (ETC) decreasing tissue damage in the lung and increasing fatty acid oxidation and glucocorticoid sensitivity in the liver. Using a liver-specific partial and acute deletion of Crif1, a critical mitoribosomal component for protein synthesis, we found that mice were protected against sepsis, an observation which was phenocopied by the transient inhibition of complex I of the ETC by phenformin. Together, we demonstrate that mitoribosome-targeting antibiotics are beneficial beyond their antibacterial activity and that mitochondrial protein synthesis inhibition leading to ETC perturbation is a mechanism for the induction of disease tolerance. These results have been published in scientific journals and disseminated to the public through traditional media and social networks. They will also serve as the bases for one clinical trial (anthracyclines, currently in its early steps) and another one at the planing stage (tetracyclines).
