PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases.
Poly(ADP-ribose) polymerases (PARPs) are defined as cell signaling enzymes that catalyze the transfer of ADP-ribose units from NAD(+) to a number of acceptor proteins. PARP-1, the best characterized member of the PARP family, which currently comprises 18 members, is an abundant nuclear enzyme implicated in cellular responses to DNA injury provoked by genotoxic stress. PARP is involved in DNA repair and transcriptional regulation and is now recognized as a key regulator of cell survival and cell death as well as a master component of a number of transcription factors involved in tumor development and inflammation. PARP-1 is essential to the repair of DNA single-strand breaks via the base excision repair pathway. Inhibitors of PARP-1 have been shown to enhance the cytotoxic effects of ionizing radiation and DNA-damaging chemotherapy agents, such as the methylating agents and topoisomerase I inhibitors. There are currently at least five PARP inhibitors in clinical trial development. Recent in vitro and in vivo evidence suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers, but also as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer-associated genes (BRCA1 and BRCA2). PARP becomes activated in response to oxidative DNA damage and depletes cellular energy pools, thus leading to cellular dysfunction in various tissues. The activation of PARP may also induce various cell death processes and promotes an inflammatory response associated with multiple organ failure. Inhibition of PARP activity is protective in a wide range of inflammatory and ischemia-reperfusion-associated diseases, including cardiovascular diseases, diabetes, rheumatoid arthritis, endotoxic shock, and stroke. The aim of this review is to overview the emerging data in the literature showing the role of PARP in the pathogenesis of cancer and inflammatory diseases and unravel the solid body of literature that supports the view that PARP is an important target for therapeutic intervention in critical illness.
Instituto de Parasitología y Biomedicina López Neyra, Consejo Superior de Investigaciones Cientificas (CSIC), Granada, Spain.
Andreína
A
Peralta-Leal
José Manuel
JM
Rodríguez-Vargas
Rocío
R
Aguilar-Quesada
María Isabel
MI
Rodríguez
José Luis
JL
Linares
Mariano Ruiz
MR
de Almodóvar
F Javier
FJ
Oliver
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy*; D019313:BRCA1 Protein / Q000172:deficiency; D024682:BRCA2 Protein / Q000172:deficiency; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000532:radiotherapy*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D053843:DNA Mismatch Repair / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000276:immunology / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D011878:Radiotherapy / Q000009:adverse effects; D015427:Reperfusion Injury / Q000188:drug therapy*
D020533:Angiogenesis Inhibitors; D000893:Anti-Inflammatory Agents; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases