Authors: C. Alarcon de la Lastra,; Villegas, I.; Sanchez-Fidalgo, S.

Source: Current Pharmaceutical Design, Volume 13, Number 9, March 2007 , pp. 933-962(30)

Publisher: Bentham Science Publishers

Abstract:

Poly(ADP-ribose) polymerase (PARP) comprise of a family of enzymes which catalyses poly(ADPribosyl) ation of DNA-binding proteins. To date, seven isoforms have been identified: PARP-1, PARP-2, PARP-3, PARP- 4 (Vault-PARP), PARP-5 (Tankyrases), PARP-7 and PARP-10 with structural domains and different functions. PARP-1, the best characterised member, works as a DNA damage nick-sensor protein that uses beta-NAD+ to form polymers of ADP-ribose and has been implicated in DNA repair, maintenance of genomic integrity and mammalian longevity. The generation of free radicals, reactive oxygen species, and peroxynitrite causes overactivation of PARP resulting in the depletion of NAD+ and ATP and consequently in necrotic cell death and organ dysfunction. PARP has also been involved in the up-regulation of numerous pro-inflammatory genes through the activation of several transcription nuclear factors. Thus, PARP plays an important role in the pathogenesis of several diseases, such as, stroke, myocardial infarction, circulatory shock, diabetes, neurodegenerative disorders, including Parkinson and Alzheimer diseases, allergy, colitis and other inflammatory disorders. Pharmacological modulation of PARP activity may constitute a suitable target to enhance the cytotoxicity of certain DNA-damaging anticancer drugs. Also, PARP inhibition may be a viable strategy to control viral infections. This review is intended to provide an appreciation of new pharmacological perspectives of these remarkable drugs, summarize novel underlying mechanisms and discuss their potential clinical implications.

Keywords: PARP; cancer; inflammation; diabetes

Document Type: Research article

DOI: http://dx.doi.org/10.2174/138161207780414241

Affiliations: 1: Departamento de Farmacologia,Facultad de Farmacia, Universidad de Sevilla, c/ Profesor Garcia Gonzalez 2, 41012 Sevilla, Spain.

Publication date: 2007-03-01

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• Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.
  
  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

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