02 May 2003 : Case report
Use of PARP inhibitors to counteract the side effects of cytotoxic drugs
B. Sumegi, P. DeresMed Sci Monit 2003; 9(1): 65-0 :: ID: 15204
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, akt. Phosphorylation
Editorial
01 April 2024 : Editorial
Editorial: Forty Years of Waiting for Prevention and Cure of HIV Infection – Ongoing Challenges and Hopes for Vaccine Development and Overcoming Antiretroviral Drug ResistanceDOI: 10.12659/MSM.944600
Med Sci Monit 2024; 30:e944600
In Press
06 Mar 2024 : Clinical Research
Comparison of Outcomes between Single-Level and Double-Level Corpectomy in Thoracolumbar Reconstruction: A ...Med Sci Monit In Press; DOI: 10.12659/MSM.943797
21 Mar 2024 : Meta-Analysis
Economic Evaluation of COVID-19 Screening Tests and Surveillance Strategies in Low-Income, Middle-Income, a...Med Sci Monit In Press; DOI: 10.12659/MSM.943863
10 Apr 2024 : Clinical Research
Predicting Acute Cardiovascular Complications in COVID-19: Insights from a Specialized Cardiac Referral Dep...Med Sci Monit In Press; DOI: 10.12659/MSM.942612
06 Mar 2024 : Clinical Research
Enhanced Surgical Outcomes of Popliteal Cyst Excision: A Retrospective Study Comparing Arthroscopic Debride...Med Sci Monit In Press; DOI: 10.12659/MSM.941102
Most Viewed Current Articles
17 Jan 2024 : Review article
Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron VariantDOI :10.12659/MSM.942799
Med Sci Monit 2024; 30:e942799
14 Dec 2022 : Clinical Research
Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase LevelsDOI :10.12659/MSM.937990
Med Sci Monit 2022; 28:e937990
16 May 2023 : Clinical Research
Electrophysiological Testing for an Auditory Processing Disorder and Reading Performance in 54 School Stude...DOI :10.12659/MSM.940387
Med Sci Monit 2023; 29:e940387
01 Jan 2022 : Editorial
Editorial: Current Status of Oral Antiviral Drug Treatments for SARS-CoV-2 Infection in Non-Hospitalized Pa...DOI :10.12659/MSM.935952
Med Sci Monit 2022; 28:e935952