Clinical perspectives of PARP inhibitors.
Poly(ADP-ribose) polymerase (PARP) activation plays a role in the pathogenesis of various cardiovascular and inflammatory diseases. At the same time, PARP activation is also relevant for the ability of cells to repair injured DNA. Thus, depending on the circumstances, pharmacological inhibitors of PARP may be able to attenuate ischemic and inflammatory cell and organ injury or may be able to enhance the cytotoxicity of antitumor agents. Both aspects of the "double-edged sword" role of PARP can be exploited for the experimental therapy of disease. As several classes of PARP inhibitors move towards clinical development, or have already entered the stage of clinical trials, we expect that in the upcoming few years, clinical proof of PARP inhibitors' therapeutic effect will be obtained in human disease. In the current short overview, we summarize the pros and cons and challenges with respect to the clinical use of PARP inhibitors, the expected clinical outcomes and potential risks. It appears that on the cytoprotective aspect of PARP, acute, life-threatening diseases (myocardial infarction, cardiopulmonary bypass in high-risk patients, and other, severe forms of ischemia-reperfusion to other organs including stroke and thoracoabdominal aneurysm repair) may represent some of the prime development indications. In the context of inhibition of DNA repair, combination of PARP inhibitors with certain antitumor agents (for example temozolomide) in patients with tumors with extremely poor prognosis are expected to provide the initial clinical results. Development of PARP inhibitors for additional indications (e.g. chronic use for the therapy of neurodegeneration and neuroinflammation, or diabetic complications) may be more challenging because of the unknown potential long-term side effects of PARP inhibitors.
Graziani
Grazia
G
Department of Neuroscience, University of Rome Tor Vergata,Via Montpellier, 1, 00133 Rome, Italy. graziani@uniroma2.it
Szabó
Csaba
C
D017209:Apoptosis / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000188:drug therapy; D019610:Cytoprotection; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D020521:Stroke / Q000188:drug therapy
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases