Abstract
Doxorubicin (DOX) is an anthracycline cancer chemotherapeutic that exhibits cumulative dose-limiting cardiotoxicity and limits its clinical utility. DOX treatment results in the development of morbid cardiac hypertrophy that progresses to congestive heart failure and death. Recent evidence suggests that during the development of DOX mediated cardiac hypertrophy, mitochondrial energetics are severely compromised, thus priming the cardiomyocyte for failure. To mitigate cumulative dose (5 mg/kg, QIW x 4 weeks with 2 weeks recovery) dependent DOX, mediated cardiac hypertrophy, we applied an orally active selenium based compound termed phenylaminoethyl selenides (PAESe) (QIW 10 mg/kg x 5) to our animal model and observed that PAESe attenuates DOX-mediated cardiac hypertrophy in athymic mice, as observed by MRI analysis. Mechanistically, we demonstrated that DOX impedes the stability of the iron-sulfur cluster biogenesis protein Frataxin (FXN) (0.5 fold), resulting in enhanced mitochondrial free iron accumulation (2.5 fold) and reduced aconitase activity (0.4 fold). Our findings further indicate that PAESe prevented the reduction of FXN levels and the ensuing elevation of mitochondrial free iron levels. PAESe has been shown to have anti-oxidative properties in part, by regeneration of glutathione levels. Therefore, we observed that PAESe can mitigate DOX mediated cardiac hypertrophy by enhancing glutathione activity (0.4 fold) and inhibiting ROS formation (1.8 fold). Lastly, we observed that DOX significantly reduced cellular respiration (basal (5%) and uncoupled (10%)) in H9C2 cardiomyoblasts and that PAESe protects against the DOX-mediated attenuation of cellular respiration. In conclusion, the current study determined the protective mechanism of PAESe against DOX mediated myocardial damage and that FXN is implicitly involved in DOX-mediated cardiotoxicity.
Highlights
Doxorubicin (DOX) is an anthracycline cancer chemotherapeutic agent that is used widely for the treatment of multiples cancers, including prostate, breast, lung, bone, and leukemias (Kuerer et al, 1999; Khan and Denmeade, 2000; Neville-Webbe et al, 2005)
Following DOX treatment, Magnetic resonance imaging (MRI) imaging and analysis revealed an increase in the left ventricular mass (1B) [t (6) 3.450; p < 0.05]
DOX treatment resulted in an enlargement in the anterolateral segment of the left ventricle by evaluation of changes associated with the left ventricular segmented regions (Figures 1A,B)
Summary
Doxorubicin (DOX) is an anthracycline cancer chemotherapeutic agent that is used widely for the treatment of multiples cancers, including prostate, breast, lung, bone, and leukemias (Kuerer et al, 1999; Khan and Denmeade, 2000; Neville-Webbe et al, 2005). DOX use is associated with the development of drug resistance and several adverse effects (Cersosimo and Hong, 1986; Lipshultz et al, 1991; Solem et al, 1996; Tada et al, 2002), including cumulative dose-dependent cardiotoxicity that leads to cardiac failure (CF) and has been reported to be one of most significant challenges associated with its clinical efficacy (Arola et al, 2000). It has been well established that energy starvation plays an important role in the mechanism underlying DOX-induced cardiac failure (Ashour et al, 2012). Studies demonstrated that DOX-induced cardiomyopathy and the eventual cardiotoxicity was caused by mitochondrial iron accumulation (Kwok and Richardson, 2004; Mouli et al, 2015). Overexpression of FXN offered significant cardioprotection against DOX exposure (Mouli et al, 2015)
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