Pyridoxamine Protects Against Cardiotoxicity After Doxorubicin Chemotherapy

Abstract

Introduction: Although doxorubicin (DOX) is an efficient anthracycline agent used to treat cancer, it induces cardiotoxicity and mortality in cancer survivors. Cardioprotection is inadequate. The vitamin B6-derivative pyridoxamine (PM) has shown to be cardioprotective in diverse cardiac diseases. Whether PM offers cardioprotection after DOX treatment is unknown. We hypothesized that PM limits cardiac impairment after DOX treatment by reducing cardiac fibrosis and inflammation.

Methods: Female Sprague Dawley rats were weekly treated with 2 mg/kg DOX or saline IV for 8 weeks. At DOX treatment onset, 2 extra groups received PM (1 g/L) via the drinking water. Echocardiographic (4D) and hemodynamic parameters were assessed at week 8, together with plasma BNP. PCR analysis was performed on left ventricular tissue to evaluate fibrosis and inflammation. Data were compared using 1-way ANOVA, Kruskal-Wallis test or 2-way ANOVA with post-hoc tests as appropriate.

Results: As shown in Table 1, cardiac impairment by DOX was prevented by PM. In addition, DOX significantly increased the expression of fibrosis markers, such as TGFβ (0.29 ± 0.02 vs. 0.69 ± 0.09 a.u., p<0.0001), LOX (0.055 ± 0.002 vs. 0.590 ± 0.174 a.u., p<0.01), collagen type 1 (0.21 ± 0.02 vs. 0.62 ± 0.11 a.u., p<0.001) and interstitial collagen (4.6 ± 0.3 vs. 7.7 ± 0.6%, p<0.001). DOX also increased the inflammation marker IL-6 (0.13 ± 0.03 vs. 0.73 ± 0.13 a.u., p<0.01). PM treatment significantly lowered all these parameters (p<0001, p<0.001, p<0.01, p<0.01 and p<0.01 respectively).

Conclusions: In conclusion, our data show that DOX causes dilated cardiomyopathy with reduced ejection fraction, accompanied by cardiac fibrosis and myocarditis. As PM limits this adverse phenotype, it could be a novel cardioprotective strategy for DOX-treated cancer patients.