Abstract
BackgroundDoxorubicin (DOX) is a very effective anticancer medication that is commonly used to treat hematological malignancies and solid tumors. Nevertheless, DOX is known to have cardiotoxic effects that may lead to cardiac dysfunction and failure. In experimental studies, female animals have been shown to be protected against DOX-induced cardiotoxicity; however, the evidence of this sexual dimorphism is inconclusive in clinical studies. Therefore, we sought to investigate whether genetic background could influence the sexual dimorphism of DOX-induced cardiotoxicity.MethodsMale and female Wistar Kyoto (WKY) and Spontaneous Hypertensive Heart Failure (SHHF) rats were used. DOX was administered in eight doses of 2 mg/kg/week and the rats were followed for an additional 12 weeks. Cardiac function was assessed by trans-thoracic echocardiography, systolic blood pressure was measured by the tail cuff method, and heart and kidney tissues were collected for histopathology.ResultsFemale sex protected against DOX-induced weight loss and increase in blood pressure in the WKY rats, whereas it protected against DOX-induced cardiac dysfunction and the elevation of cardiac troponin in SHHF rats. In both strains, female sex was protective against DOX-induced nephrotoxicity. There was a strong correlation between DOX-induced renal pathology and DOX-induced cardiac dysfunction.ConclusionsThis study highlights the importance of studying the interaction between sex and genetic background to determine the risk of DOX-induced cardiotoxicity. In addition, our findings suggest that DOX-induced nephrotoxicity may play a role in DOX-induced cardiac dysfunction in rodent models.
Highlights
Doxorubicin (DOX) is a very effective anticancer medication that is commonly used to treat hematological malignancies and solid tumors
Since pre-existing cardiovascular disease is considered a significant risk factor for more severe DOX-induced cardiotoxicity [16] and we have shown that the genetic predisposition to cardiovascular diseases made male Spontaneous Hypertensive Heart Failure (SHHF) rats more susceptible to DOX-induced cardiac dysfunction than Wistar Kyoto (WKY) rats [25], we sought to investigate the interplay between genetic predisposition to cardiovascular diseases and sexual dimorphism in the context of DOX-induced cardiotoxicity
We show that there is a strong correlation between DOX-induced renal injury and DOX-induced cardiac dysfunction, which highlights the importance of studying DOX-induced nephrotoxicity simultaneously with the well-known cardiotoxicity in rodent models
Summary
Doxorubicin (DOX) is a very effective anticancer medication that is commonly used to treat hematological malignancies and solid tumors. Female animals have been shown to be protected against DOX-induced cardiotoxicity; the evidence of this sexual dimorphism is inconclusive in clinical studies. We sought to investigate whether genetic background could influence the sexual dimorphism of DOX-induced cardiotoxicity. Increased survivorship is promising, these survivors may suffer from long term adverse effects of anticancer medications. Several anticancer agents may cause acute and/or delayed cardiotoxic side effects [2]. Several factors can increase the risk of cardiotoxicity after anthracycline treatment, including total cumulative dose, co-administration of other cardiotoxic agents, age, sex, and genetic predisposition to cardiovascular disease [14,15,16,17].
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