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Open Access Highly Accessed Research article

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

Clément Guillot125, Vincent Favaudon34, Zdenko Herceg5, Charlotte Sagne345, Sylvie Sauvaigo6, Philippe Merle127, Janet Hall34 and Isabelle Chemin12*

Author Affiliations

1 UMR INSERM U1052 CNRS 5286, CRCL, 151 Cours A Thomas, Lyon F-69008, France

2 Université Lyon-1, Villeurbanne F-69622, France

3 Institut Curie, Bats 110–112 Centre Universitaire, Orsay F-91405, France

4 Inserm U612, Bats 110–112 Centre Universitaire, Orsay F-91405, France

5 International Agency for Research on Cancer, 150 cours Albert Thomas, F-69424, Lyon Cedex 03, France

6 Laboratoire Lésions des Acides Nucléiques, CEA, DSM/INAC/SCIB, UMR-E3 CEA/UJF-Grenoble 1, 17 rue des Martyrs, Grenoble F-38054, France

7 Hospices Civils de Lyon, Service d’Hépatologie et de Gastroentérologie, Groupement Hospitalier Lyon Nord, Lyon, France

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BMC Cancer 2014, 14:603  doi:10.1186/1471-2407-14-603

Published: 20 August 2014

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:
Hepatocellular carcinoma; Poly(ADP-ribose) polymerases inhibitors; Radiation therapy