title: PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models.
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.
authors.forename: Clément
authors.initials: C
authors.lastname: Guillot
authors.forename: Vincent
authors.initials: V
authors.lastname: Favaudon
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.forename: Charlotte
authors.initials: C
authors.lastname: Sagne
authors.forename: Sylvie
authors.initials: S
authors.lastname: Sauvaigo
authors.forename: Philippe
authors.initials: P
authors.lastname: Merle
authors.forename: Janet
authors.initials: J
authors.lastname: Hall
authors.affiliation: UMR INSERM U1052 CNRS 5286, CRCL, 151 Cours A Thomas, Lyon F-69008, France. isabelle.chemin@inserm.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Chemin
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000628:therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000628:therapy; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D011838:Radiation-Sensitizing Agents; C521013:veliparib; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases