PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models

Clément Guillot 1 Vincent Favaudon 2 Zdenko Herceg 1 Charlotte Sagne 2, 1 Sylvie Sauvaigo 3 Philippe Merle 4, 1 Janet Hall 2 Isabelle Chemin 1, *
* Auteur correspondant
1 CRCL - Centre de Recherche en Cancérologie de Lyon
2 Génotoxicologie, signalisation et radiothérapie expérimentale
3 LAN - Laboratoire Lésions des Acides Nucléiques
SCIB - UMR E3 - Service de Chimie Inorganique et Biologique : DSM/INAC/SCIB
4 Service d'Hépatologie et de Gastroentérologie
Abstract : Background: Hepatocellular carcinoma is the third cause of cancer related death for which new treatment strategies are needed. Targeting DNA repair pathways to sensitize tumor cells to chemo-or radiotherapy is under investigation for the treatment of several cancers with poly(ADP-ribose) polymerase (PARP) inhibitors showing great potential. The aim of this preclinical study was to evaluate the expression of PARP and PARG genes in a panel of liver cancer cell lines and primary human hepatocytes, their DNA repair capacity and assess the impact on cell survival of PARP inhibitors alone and in combination with radiotherapy. Methods: Quantitative PCR was used to measure PARP-1, −2, −3 and PARG mRNA levels and western blotting for PARP-1 protein expression and ADP-ribose polymer formation after exposure of cells to doxorubicin, a topoisomerase II poison. DNA repair capacity was assessed using an in vitro DNA lesion excision/synthesis assay and the effects on cell killing of the PARP inhibitor ABT-888 alone and in combination with ionizing radiation using clonogenic survival. Results: Although a wide range in expression of the PARPs and PARG was found correlations between PARP-1 and PARP-2 mRNA levels and PARP-1 mRNA and protein levels were noted. However these expression profiles were not predictive of PARP activity in the different cell lines that also showed variability in excision/synthesis repair capacity. 4 of the 7 lines were sensitive to ABT-888 alone and the two lines tested showed enhanced radiosensitivity in the presence of ABT-888. Conclusions: PARP inhibitors combined with radiotherapy show potential as a therapeutic option for hepatocellular carcinoma.
Keywords : Radiation therapy Poly(ADP-ribose) polymerases inhibitors Hepatocellular carcinoma
Type de document :
Article dans une revue
BMC Cancer, BioMed Central, 2014, 14, pp.603. 〈10.1186/1471-2407-14-603〉
Liste complète des métadonnées

Littérature citée [33 références]  Voir  Masquer  Télécharger
http://www.hal.inserm.fr/inserm-01122364
Contributeur : Christine Dupuis <>
Soumis le : mardi 3 mars 2015 - 16:50:51
Dernière modification le : mercredi 25 juillet 2018 - 16:34:01
Document(s) archivé(s) le : samedi 12 septembre 2015 - 22:55:31

Fichier

1471-2407-14-603.pdf
Fichiers produits par l'(les) auteur(s)

Identifiants

Collections

CEA | HCL | FNCLCC | CURIE | INAC-SCIB | DSM-INAC | UGA | PSL | UNIV-LYON1 | CEA-DRF | CRCL

Citation

Clément Guillot, Vincent Favaudon, Zdenko Herceg, Charlotte Sagne, Sylvie Sauvaigo, et al.. PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models. BMC Cancer, BioMed Central, 2014, 14, pp.603. 〈10.1186/1471-2407-14-603〉. 〈inserm-01122364〉

Exporter

BibTeX TEI DC DCterms EndNote

Partager

Métriques

Consultations de la notice

284

Téléchargements de fichiers

221

Contact

support.ccsd.cnrs.fr
hal.support@ccsd.cnrs.fr
Logo CCSD