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Unravelling cardiotoxic mechanisms of anti-cancer doxorubicin

Most anti-cancer drugs show low specificity, affecting normal tissues as well and causing severe cytotoxicity. European researchers discovered that doxorubicin cardiotoxic action was largely due to impaired metabolic and stress signalling.
Unravelling cardiotoxic mechanisms of anti-cancer doxorubicin
Anthracyclines are compounds that bind within the double helix structure of the DNA, inducing cell killing. The most common anthracycline is doxorubicin, a chemotherapeutic drug used extensively as an anti-cancer treatment. Although its serious side-effect on cardiac function has been extensively documented, the way in which doxorubicin causes cardiotoxicity remains unexplored.

This led scientists of the EU-funded ANTHRAPLUS project to investigate the mechanisms by which doxorubicin is especially harmful to the heart. The running hypothesis was that it mediates changes in cell signalling, depletes energy, and induces oxidative and genotoxic stress.

Researchers followed a proteomics approach to identify new phosphorylation events mediating the response to doxorubicin. In parallel, they focused on specific pathways, including signalling by LKB1, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Akt and mitogen-activated protein kinases (MAPK).

These methods were applied both in vivo and ex vivo on a Langendorff perfused rat heart. The phosphoproteomic approach identified 22 proteins that presented an altered phosphorylation status and were involved, among others, in energy metabolism and sarcomere structure and function. These changes could explain some of the symptoms of cardiac dysfunction following doxorubicin treatment.

The targeted analysis highlighted a doxorubicin-mediated inhibition of the key cellular energy sensor and regulator, AMPK. This was due mainly to cross talk with the Akt and MAPK signalling pathways.

ANTHRAPLUS findings shed new light onto the molecular and cellular aetiology of doxorubicin-related cardiotoxicity. Information generated has particularly high clinical relevance given the success of this drug in cancer chemotherapy, and provides a molecular basis as to how to protect the heart after doxorubicin administration.

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