BPM 31510 decreases doxorubicin-induced cardiomyopathy

Doxorubicin is a commonly used antineoplastic agent for treatment of cancers in adults and children. Despite its high efficacy in the treatment of various cancers, doxorubicin confers dose-limiting cardiogenic toxicity in both populations and associated with EKG changes. In a subset of patients, this effect on EKG is transient, however a significant number of patients will develop cardiomyopathy refractory to conventional treatment. Mitochondrial damage in the cardiomyocytes is the first hallmark of doxorubicin-induced cardiomyopathy. It has been suggested that lipid peroxidation may play a pivotal role in its pathophysiology by affecting the mitochondria through formation of reactive oxygen species. This theory is supported by the presence of markers of lipid peroxidation after doxorubicin administration in the blood. Coenzyme Q10 is found within the membranes of the mitochondria, lysosomes and the Golgi apparatus, and also acts as a powerful antioxidant and inhibitor of lipid peroxidation. BPM 31510 is an intravenous formulation of coenzyme Q10 in a proprietary nanodispersion formulation with ability to selectively deliver high concentrations of Coenzyme Q10 to targets tissues and organelles including the mitochondria. In this study, Sprague Dawley rats were used as model system to determine the effect of intravenous BPM31510 on doxorubicin-mediated cardiomyopathy. Lethality of doxorubicin was observed when rats were injected intraperitoneally 20 mg total dose, with a schedule of 10 mg/kg/day for two days. On day 30, signs of morbidity were present, such as cachexia and a decrease in the size of the heart was documented following necropsy. Concomitant administration of BPM31510 resulted in a modest but significant increase in lifespan in the doxorubicin treated animals (p 0.025). In contrast, pretreatment with intravenous BPM31510 followed by doxorubicin dosing was associated with significant decline in mortality, with as many as sixty percent of animals surviving past 30 days (p<0.01). The potential mechanism(s) underlying the effect of long-term use of BPM31510 on doxorubicin-induced cardiotoxicity was investigated. Rats with a protracted regimen of doxorubicin died between days 25 and 30, whereas as previously observed, BPM 31510 had a significant impact on survival (p=0.005). Increased survival in the BPM31510 treated group was associated with significant decreases in alterations of heart morphology and biochemical parameters of oxidative stress. Taken together, the data suggests that intravenous BPM31510 has the potential to mitigate doxorubicin-mediated mortality