Poly(ADP-ribose)polymerase-1 (PARP-1) in carcinogenesis: potential role of PARP inhibitors in cancer treatment.
Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear, zinc-finger, deoxyribonucleic acid (DNA)-binding protein that detects specifically DNA strand breaks generated by different genotoxic agents. Whereas activation of PARP-1 by mild genotoxic stimuli facilitates DNA repair and cell survival, severe DNA damage triggers different pathways of cell death, including PARP-mediated cell death through the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus. Pharmacological inhibition or genetic ablation of PARP-1 results in a clear benefit in cancer treatment by different mechanisms, including selective killing of homologous recombinationdeficient tumor cells, downregulation of tumor-related gene expression, and decrease in the apoptotic threshold in the cotreatment with chemo- and radiotherapy. We summarize in this review the findings and concepts for the role of PARP-1 and poly(ADP-ribosylation) in the regulation of carcinogenesis and some of the preclinical and clinical data available for these agents, together with the challenges facing the clinical development of these agents.
Instituto de Parasitología y Biomedicina López Neyra, Spain.
A
A
Peralta-Leal
M I
MI
Rodríguez
F J
FJ
Oliver
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases