Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction

Inotek Pharmaceuticals Corp, Beverly, Mass 01915, USA.
Circulation (Impact Factor: 14.95). 03/2003; 107(6):896-904. DOI: 10.1161/01.CIR.0000048192.52098.DD
Source: PubMed

ABSTRACT Increased oxidative stress and dysregulation of nitric oxide have been implicated in the cardiotoxicity of doxorubicin (DOX), a commonly used antitumor agent. Peroxynitrite is a reactive oxidant produced from nitric oxide and superoxide in various forms of cardiac injury. Using a novel metalloporphyrinic peroxynitrite decomposition catalyst, FP15, and nitric oxide synthase inhibitors or knockout mice, we now delineate the pathogenetic role of peroxynitrite in rodent models of DOX-induced cardiac dysfunction.
Mice received a single injection of DOX (25 mg/kg IP). Five days after DOX administration, left ventricular performance was significantly depressed, and high mortality was noted. Treatment with FP15 and an inducible nitric oxide synthase inhibitor, aminoguanidine, reduced DOX-induced mortality and improved cardiac function. Genetic deletion of the inducible nitric oxide synthase gene was also accompanied by better preservation of cardiac performance. In contrast, inhibition of the endothelial isoform of nitric oxide synthase with N-nitro-L-arginine methyl ester increased DOX-induced mortality. FP15 reduced the DOX-induced increase in serum LDH and creatine kinase activities. Furthermore, FP15 prevented the DOX-induced increase in lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation in the heart but not NAD(P)H-driven superoxide generation. Peroxynitrite neutralization did not interfere with the antitumor effect of DOX. FP15 also decreased ischemic injury in rats and improved cardiac function and survival of mice in a chronic model of DOX-induced cardiotoxicity.
Thus, peroxynitrite plays a key role in the pathogenesis of DOX-induced cardiac failure. Targeting peroxynitrite formation may represent a new cardioprotective strategy after DOX exposure or in other conditions associated with peroxynitrite formation, including myocardial ischemia/reperfusion injury.

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Available from: Michael S Wolin, Aug 27, 2015
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    • "The mechanism of Dox-induced cardiotoxicity is not fully understood. However, Dox-induced production of reactive oxygen species (ROS) has been implicated as critical for subsequent cardiac myocyte apoptosis and heart damage (Li and Singal, 2000; Zhou et al., 2001; Pacher et al., 2003). The chemotherapeutic efficacy of Dox relies on its ability to kill cancer cells by activating the ATM–p53 apoptosis pathways (Evan, 1997; Canman et al., 1998; Khanna et al., 1998; Bakkenist and Kastan, 2003; Iliakis et al., 2003), which is also responsible for Dox-induced cardiotoxicity as inhibition of components of this pathway protects against Doxinduced heart injury in mice (Liu et al., 2004; Shizukuda et al., 2005; Yoshida et al., 2009; Zhu et al., 2009). "
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