Abstract

Many antitumor drugs (doxorubicin (DOX), cisplatin (CisP), and AZT) induce oxidative stress in several tissues, which can contribute to their side effects [1–3]. Oxidative stress can trigger DNA damage and poly(ADP-ribose) polymerase (PARP) activation, which may contribute to an important pathway of cell dysfunction and tissue injury under the conditions associated with oxidative insult [4]. Oxidative injury is a major factor implicated in the cardiotoxicity of doxorubicin (DOX), in the cardiotoxicity of AZT and in the nephrotoxicity caused by cisplatin. Thus, we and others hypothesized that the activation of PARP may contribute to the antitumor drug-induced cardiotoxicity and cisplatin-induced nephrotoxicity. DOX administration in PARP-1+/+ mice depressed left ventricular performance, while the heart function of PARP-1–/– ones and PARP-1+/+ mice treated with PJ34 (1) or HO-3089 (experimental PARP inhibitors) was deteriorated only to a smaller extent. Our data showed that PARP inhibitors activated cardiac Akt and GSK-3b, which may have contributed to their protective effect. Cisplatin-induced kidney dysfunction was prevented by another PARP inhibitor, BGP-15. The cisplatin-caused edema formation was reversed as showed by MRI analysis. High-energy phosphate intermediate levels were reestablished by BGP-15 treatment demonstrated in vivo by localized NMR spectroscopy, which was correlated with the diminished ADP-ribosylation in BGP-15-treated mice [3]. However, the anti-cytostatic effect of cisplatin was not compromised. These data indicate that PARP inhibitors may be applied in combination with cytostatic drugs and their side effects in the heart and kidney can be attenuated without compromising their antitumor efficacy. References: 1.Pacher P, Liaudet L, Bai P et al: Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure. J Pharmacol Exp Ther, 2002 Mar; 300(3): 862-7 2.Szabados E, Fisher MG, Toth K et al: Role of reactive oxygen species and poly-ADP-ribose polymerase in the development of AZT-induced cardiomyopathy in rat. Free Rad Biol & Med, 1999; 26: 309-317 3.Rabloczky G, Jaszlits L, Bárdos G, et al: Chemoprotective Effect Of A Novel PARP Inhibitor. Therapeutic utilities of PARP inhibitors, 2002; 223-228 4.Halmosi R, Berente Z, Osz E et al: Effect of Poly (ADP-Ribose) Polymerase Inhibitors on the Ischemia-Reperfusion Induced Oxidative Cell Damage and Mitochondrial Metabolism in Langendorff Heart Perfusion System. Mol Pharmacol, 2001; 59: 1497-1505

Keywords: PARP, ADP-ribose, cancer, Doxorubicin, akt. Phosphorylation