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Interference of anthracyclines with cardiac energy signalling: implications for drugs, cardiotoxicity and oncogenic growth

Final Activity Report Summary - ANTHRAWES (Interference of anthracyclines with cardiac energy signalling: implications for drugs, cardiotoxicity and oncogenic growth)

Drugs of the anthracycline group, in particular doxorubicin (Adriamycin), are among the most effective and extensively used anti-cancer agents. However, their use is limited by a significant risk of cardiotoxicity, whose molecular mechanisms are still not entirely clear. The aim of the project was to improve our understanding of these mechanisms, in particular in regard to impaired cellular energy metabolism, which is especially harmful to myocardium, requiring continuous energy supply to sustain contractile performance.

A genome-wide analysis of antracycline-induced changes in gene expression and the proteome/phospho-proteome was combined with a targeted analysis of the AMPK signalling cascade, emerging as the central signalling pathway in regulating energy metabolism. Using a perfused heart model and cultured cardiomyocytes, we have obtained further evidence that doxorubicin decreases basal phosphorylation of AMPK and related up- and downstream kinases, while the AKT pathway is activated. Doxorubinin-induced changes in the transcriptome revealed further putative toxicity mechanisms, in particular rapid down-regulation of many single genes and entire pathways involved in the cellular response to stress like heat shock or oxidative, hypoxic, and genotoxic stress.

Our results propose that a blunted response to stress or reduced "danger signalling" leads among others to impaired cellular energetics and is a prime component of toxic doxorubicin action and can drive cardiac cells into pathology. Protective effects of creatine and phosphocreatine were demonstrated.