Streptozotocin-induced hyperglycemia unmasks cardiotoxicity induced by doxorubicin

Late-onset cardiotoxicity induced by anthracyclines occurs years to decades after completion of anti-cancer therapy and is associated with increased morbi-mortality of cancer survivors. Chemotherapy at the time of treatment probably causes cardiac damages for which the juvenile heart compensate. Co-morbidities happening in the adulthood such as type 1 diabetes (DT1), affect the heart and thus can unmask chemotherapy induced cardiotoxicity. To prove our hypothesis, we induced hyperglycemia [Streptozotocin treatment (STZ), 50 mg/kg/day for 5 days] in 11 weeks old mice who previously received doxorubicin treatment (Dox, 3 mg/kg) when they were six-weeks old. Interestingly, streptozotocin-induced hyperglycemia in Dox-pretreated mice (Dox-STZ) induced a higher mortality (p < 0.05) and more severe cardiac dysfunction (p < 0.0001) when compared with mice receiving Dox or STZ alone. Apoptosis evaluated by caspase 3 protein expression and Bax/Bcl2 genes expression was higher in Dox-STZ mice compared to STZ or Dox alone. While Dox and STZ independently induced capillary rarefaction, cardiomyocytes atrophy was only induced by STZ. Furthermore, Sirius-red staining of cardiac sections showed higher fibrosis levels (p < 0.0001) in Dox-STZ compared to Dox or STZ alone. All together, these results demonstrate that STZ precipitates and unmask cardiac dysfunction in previously treated Dox animals.