Project R-10248

Chemotherapy-induced cardiotoxicity: time for a chAnGE of stRAteGiEs. (Research)

The cancer patients of today are the cardiac patients of tomorrow. Chemotherapy is lifesaving but induces cardiac dysfunction. Indeed, doxorubicin is an effective anti-cancer drug but causes adverse morphological, functional and ultrastructural changes of the heart. At high dose, the chance of getting doxorubicin-induced cardiac failure rises to 48%. Although oxidative stress is thought to be the underlying mechanism, trials using antioxidants remain disappointing and insight into the disease is incomplete. This leads to inadequate treatment of this specific patient population. Recently, irreversiblydamaged proteins formed by the addition of sugar molecules (i.e. AGEs) were found in the hearts of doxorubicin-treated rats. Additionally, AGEs-induced cardiac failure, independent of doxorubicin treatment, shares common traits with doxorubicininduced cardiac failure in rats. However, the contribution of the receptor of AGEs (i.e. RAGE) in this setting is unknown. In this project, I hypothesize that AGEs formation and/or RAGE receptor activation after doxorubicin chemotherapy impairs structural and functional properties of cardiac muscle cells. To closely model the clinical situation, I induce breast cancer in rats, treat them with doxorubicin and examine the contribution of AGEs and RAGE in this setting. In the long term, AGEs and/or RAGE can become a new target to prevent or treat chemotherapy-induced cardiac failure.

01 November 2019 - 31 October 2020