Doxorubicin targets multiple players: A new view of an old problem.

Anthracycline cardiotoxicity remains a serious problem in paediatric and adult cancer survivors, and the advancement of cardio-oncology is a necessary step for an effective care of the patients that experience adverse cardiovascular effects. In this review, we discuss the multiple instruments used by clinicians that constitute the current strategies for primary and secondary prevention aiming at contrasting the onset of early and late doxorubicin-induced cardiotoxic events. The importance of early detection of cardiotoxicity and the following pharmacological therapy has been acknowledged with the emphasis put on impaired diastolic function, an increasingly recognized precocious sign of doxorubicin cardiotoxicity with an emerging scientific and clinical interest. We highlight the involvement of progenitor cells of cardiac and extra-cardiac origin as well as multiple cardiac cell types (fibroblasts and vasculature cells), focusing on molecular signals involved in cellular injury and response. Oxidative stress, DNA damage, senescence and cell death are established mechanisms driving anthracycline toxicity, but the comprehension of their relative weight on affecting specific cell type behaviour remains to be consolidated. The contribution of these crucial stressors and the emerging tools for preserving cell function are discussed.