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PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models
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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153905/ https://www.ncbi.nlm.nih.gov/pubmed/25139788 http://dx.doi.org/10.1186/1471-2407-14-603 |
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author | Guillot, Clément Favaudon, Vincent Herceg, Zdenko Sagne, Charlotte Sauvaigo, Sylvie Merle, Philippe Hall, Janet Chemin, Isabelle |
author_facet | Guillot, Clément Favaudon, Vincent Herceg, Zdenko Sagne, Charlotte Sauvaigo, Sylvie Merle, Philippe Hall, Janet Chemin, Isabelle |
author_sort | Guillot, Clément |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4153905 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-41539052014-09-05 PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models Guillot, Clément Favaudon, Vincent Herceg, Zdenko Sagne, Charlotte Sauvaigo, Sylvie Merle, Philippe Hall, Janet Chemin, Isabelle BMC Cancer Research Article 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. BioMed Central 2014-08-20 /pmc/articles/PMC4153905/ /pubmed/25139788 http://dx.doi.org/10.1186/1471-2407-14-603 Text en © Guillot et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Guillot, Clément Favaudon, Vincent Herceg, Zdenko Sagne, Charlotte Sauvaigo, Sylvie Merle, Philippe Hall, Janet Chemin, Isabelle PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models |
title | PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models |
title_full | PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models |
title_fullStr | PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models |
title_full_unstemmed | PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models |
title_short | PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models |
title_sort | parp inhibition and the radiosensitizing effects of the parp inhibitor abt-888 in in vitro hepatocellular carcinoma models |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153905/ https://www.ncbi.nlm.nih.gov/pubmed/25139788 http://dx.doi.org/10.1186/1471-2407-14-603 |
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