ANTHRAPLUS

Doxorubicin-induced impairment of metabolic and stress signaling: a culprit of cardiotoxic action of the drug?

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 Obiettivo del progetto (Objective)

'Anthracyclines, in particular doxorubicin, are the most effective anticancer drugs. However, their serious side effect is a cardiotoxicity, which is not entirely understood. We propose a novel hypothesis, namely that anthracycline-induced cardiac damage is related to impaired cellular responses to energy depletion, and possibly also to other forms of stress (oxidative, genotoxic), inducing a “catastrophe”, fatal for cardiac (and cancer) cells. The aim of the project is to verify this hypothesis in different models: perfused heart, cultured cardiomyocytes, and an in vivo model of cardiotoxicity newly established in our group, the doxorubicin-treated rat. Our project will integrate: (i) a non-biased phosphoproteomic approach extending our transcriptomic study and aiming at the identification of new phosphorylation events mediating response to doxorubicin; (ii) a targeted approach focusing on pathways identified by our targeted and non-biased in vitro studies, as e.g. signaling by LKB1-AMPK-mTOR, MAPK, HIF, VEGF, and NDPK, a metabolic kinase that we have recently identified as doxorubicin target. We will analyse the effects of doxorubicin on these pathways (including gene and protein expression, phosphorylation, activity) and their consequences for cardiac function, energy state, apoptotic status, and response to an additional stress (ischemia). This multidisciplinary project will combine biophysical, biochemical, molecular, physiological and systems biology (phosphoproteomics, modeling) state-of-the-art approaches. We expect to identify new signaling pathways mediating doxorubicin cardiotoxic action. Further integration of the fellow with the host will allow full valorisation of projects initiated during the present Marie-Curie Fellowship, further supervision of PhD and master students, and access to a permanent position in Grenoble at the group leader level. This would enable the fellow to pursue a dual academic career with her spouse at the same geographic location.'

Introduzione (Teaser)

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.

Descrizione progetto (Article)

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.