The therapeutic potential of poly(ADP-ribose) polymerase inhibitors

László Virág, Csaba Szabo

Research output: Contribution to journalArticle

1102 Citations (Scopus)

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosylating) enzymes. PARP-1 is an abundant nuclear protein functioning as a DNA nick-sensor enzyme. Upon binding to DNA breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors, and PARP itself. Poly(ADP-ribosylation) contributes to DNA repair and to the maintenance of genomic stability. On the other hand, oxidative stress-induced overactivation of PARP consumes NAD+ and consequently ATP, culminating in cell dysfunction or necrosis. This cellular suicide mechanism has been implicated in the pathomechanism of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis, and various other forms of inflammation. PARP has also been shown to associate with and regulate the function of several transcription factors. Of special interest is the enhancement by PARP of nuclear factor κB-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Herein we review the double-edged sword roles of PARP in DNA damage signaling and cell death and summarize the underlying mechanisms of the anti-inflammatory effects of PARP inhibitors. Moreover, we discuss the potential use of PARP inhibitors as anticancer agents, radiosensitizers, and antiviral agents.

Original languageEnglish (US)
Pages (from-to)375-429
Number of pages55
JournalPharmacological Reviews
Volume54
Issue number3
DOIs
StatePublished - Sep 2002
Externally publishedYes

Fingerprint

Nuclear Proteins
NAD
Adenosine Diphosphate
Transcription Factors
Enzymes
Traumatic Shock
Adenosine Diphosphate Ribose
Nervous System Trauma
Single-Stranded DNA Breaks
DNA Breaks
Autoimmune Experimental Encephalomyelitis
Genomic Instability
Colitis
Chemokines
DNA Repair
Antineoplastic Agents
Histones
Suicide
DNA Damage
Arthritis

ASJC Scopus subject areas

  • Pharmacology

Cite this

The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. / Virág, László; Szabo, Csaba.

In: Pharmacological Reviews, Vol. 54, No. 3, 09.2002, p. 375-429.

Research output: Contribution to journalArticle

Virág, László ; Szabo, Csaba. / The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. In: Pharmacological Reviews. 2002 ; Vol. 54, No. 3. pp. 375-429.
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