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

BMC Cancer

Clément Guillot³  Vincent Favaudon¹  Zdenko Herceg³  Charlotte Sagne³  Sylvie Sauvaigo⁵  Philippe Merle²  Janet Hall¹  Isabelle Chemin⁴ 

[1] Inserm U612, Bats 110–112 Centre Universitaire, Orsay F-91405, France

[2] Hospices Civils de Lyon, Service d’Hépatologie et de Gastroentérologie, Groupement Hospitalier Lyon Nord, Lyon, France

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

[4] Université Lyon-1, Villeurbanne F-69622, France

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

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

Others  :  1134787
DOI  :  10.1186/1471-2407-14-603

 received in 2014-03-26, accepted in 2014-08-06,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Guillot et al.; licensee BioMed Central Ltd.

【 图 表 】

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