[From poly(ADP-ribose) discovery to PARP inhibitors in cancer therapy].

Abstract

Poly(ADP-ribosyl)ation is a post-translational modification catalyzed by poly(ADP-ribose) polymerases. PARP-1 is a molecular sensor of DNA breaks, playing a key role in the spatial and temporal organization of their repair, contributing to the maintenance of genome integrity and cell survival. The fact that PARP inhibition impairs efficacy of break repair has been exploited as anticancer strategies to potentiate the cytotoxicity of anticancer drugs and radiotherapy. Numerous clinical trials based on this innovative approach are in progress. PARP inhibition has also proved to be exquisitely efficient to kill tumour cells deficient in double strand break repair by homologous recombination, such as cells mutated for the breast cancer early onset genes BRCA1 or BRCA2, by synthetic lethality. Several phase III clinical trials are in progress for the treatment of breast and ovarian cancers with BRCA mutations and the PARP inhibitor olaparib has just been approved for advanced ovarian cancers with germline BRCA mutation. This review recapitulates the history from the discovery of poly(ADP-ribosyl)ation reaction to the promising therapeutic applications of its inhibition in innovating anticancer strategies. Benefits, hopes and obstacles are discussed.

• Authors: Valérie Schreiber, Giuditta Illuzzi, Eléa Héberlé, Françoise Dantzer
• Journal: Bulletin du cancer (Bull Cancer) Vol. 102 Issue 10 Pg. 863-73 (Oct 2015) ISSN: 1769-6917 [Electronic] France
• Vernacular Title: De la découverte du poly(ADP-ribose) aux inhibiteurs PARP en thérapie du cancer.
• PMID: 26384693 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• olaparib

Topics

• Antineoplastic Agents (therapeutic use)
• Breast Neoplasms (drug therapy, genetics)
• Clinical Trials, Phase III as Topic
• DNA Breaks, Double-Stranded
• DNA Repair (drug effects)
• Drug Discovery
• Female
• Genes, BRCA1
• Genes, BRCA2
• Humans
• Mutation
• Ovarian Neoplasms (drug therapy, genetics)
• Phthalazines (pharmacology)
• Piperazines (pharmacology)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors (therapeutic use)
• Poly(ADP-ribose) Polymerases (physiology)