There is solid and increasing experimental evidence for the role of oxidative stress, DNA injury and the activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) in the pathogenesis of cardiac myocyte injury induced by various cytotoxic drugs. We hypothesize that the PARP pathway is involved in the cardiotoxic action of the cytotoxic anti-cancer drug doxorubican. Since cardiotoxicity is the main limiting factor, which restricts the use of this powerful approaches to counteract this toxicity are of great practical importance. In this proposal, we present evidence that (1) the developmental of doxorubican-induced myocardial depression is associated with the expression of iNOS and the production of peroxynitrite in the myocardium; (2) that PARP activation participate in free-radical in free-radical mediated myocardial injury; (3) that certain forms of drug-induced myocardial depression are associated with PARP activation in the myocardium and (4) that PARP deficient mice are resistant against doxorubican-induced myocardial depression. Using a combination approach of PARP deficient mice and potent pharmacological PARP inhibitors, here we proposed to (1) investigated the role of PARP in doxorubican-induced cardiotoxicity in rodent hearts in vivo; (2) to explore the molecular mechanisms of doxorubican- induced cardiotoxicity in cardiac myocytes in vitro, with focus on the involvement of PARP and (3) to investigated whether PARP inhibition influences the cytotoxicity of doxorubican in various human cancer cells in vitro. The current project will extend our understanding on the mechanism of doxorubican-induced cardiotoxicity, and will facilitate the preclinical development of potent PARP inhibitors to ameliorate this severe side effects of doxorubican.
The annual anticipated revenues for an effective therapeutic to prevent anti-cancer-drug induced cardiodepression is over $100 million in the US alone.
| Bai, Peter; Mabley, Jon G; Liaudet, Lucas et al. (2004) Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity. Oncol Rep 11:505-8 |
| Pacher, Pal; Liaudet, Lucas; Bai, Peter et al. (2003) Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation 107:896-904 |
