In the heart of cardio-oncology: the targets and biomarkers of anticancer drugs cardiotoxicity

The cardiotoxicity of anticancer drugs is the second leading cause of death in cancer patients. Among other adverse effects, left ventricular ejection fraction decrease or heart failure emerge after anticancer treatments comprising old or new targeted therapies. In the last few years, our group has been trying to unveil the cardiac adverse outcome pathways of classic chemotherapeutic agents, mainly focusing on two topoisomerase inhibitors, mitoxantrone and doxorubicin.

Mitoxantrone and doxorubicin both cause cumulative dose cardiotoxicity and were tested in in vitro and in pre-clinical models. Results obtained in mice and rats, following a clinical relevant dosing scheme, were mimicked in vitro and demonstrated that those drugs change cellular redox homeostasis and promote inflammation, although in different biomarkers. Moreover, autophagy and energetic pathways were affected, the first mainly after mitoxantrone treatments and the latter when doxorubicin was used. Thus, distinct cardiac fingerprints for these two drugs exist.

In conclusion, although their clinical cardiac effects are similar in humans, mitoxantrone and doxorubicin have different initiating cardiotoxic events. These were revealed taking into account the use of proper experimental models, clinical relevant concentrations and Omics methods. These data are of the essence to promote drug specific cardioprotective measures in the future, for patients treated with these drugs.

VMC acknowledges funding of Fundação para a Ciência e Tecnologia (FCT), IP, under Norma Transitória DL57/2016/CP1334/CT0006. This work is funded by project UIDP/04378/2020 of UCIBIO and project LA/P/0140/2020 of i4HB.