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Antagonism of Bcl-X(L) is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells

BACKGROUND: BH3 mimetics are a class of drugs that antagonize the Bcl-2 family of apoptosis inhibitors. We have previously shown that these compounds can potentiate the activity of carboplatin against several ovarian cancer cell lines. However, recent clinical studies have highlighted that BH3 mimet...

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Autores principales: Abed, Mohammed Najim, Abdullah, Marwan Ibrahim, Richardson, Alan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832520/
https://www.ncbi.nlm.nih.gov/pubmed/27080533
http://dx.doi.org/10.1186/s13048-016-0234-y
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author Abed, Mohammed Najim
Abdullah, Marwan Ibrahim
Richardson, Alan
author_facet Abed, Mohammed Najim
Abdullah, Marwan Ibrahim
Richardson, Alan
author_sort Abed, Mohammed Najim
collection PubMed
description BACKGROUND: BH3 mimetics are a class of drugs that antagonize the Bcl-2 family of apoptosis inhibitors. We have previously shown that these compounds can potentiate the activity of carboplatin against several ovarian cancer cell lines. However, recent clinical studies have highlighted that BH3 mimetics which antagonise Bcl-X(L) are associated with significant thrombocytopenia. This has led to the development of ABT-199 which specifically inhibits Bcl-2. Unfortunately, Bcl-X(L) appears to be more frequently deregulated in ovarian cancer than Bcl-2. We therefore compared the ability of ABT-199, and the Bcl-X(L) selective compound WEHI-539, to potentiate the activity of carboplatin in ovarian cancer cell lines. METHODS: WEHI-539, ABT-737 and ABT-199 were tested in combination with carboplatin using a panel of 6 ovarian cancer cell lines. The activity of the drugs was evaluated using cell growth assays, staining with trypan bue and measurement of apoptosis by measuring caspase 3/7 activity, PARP cleavage and annexin-V/propidium iodide staining. RESULTS: We found that WEHI-539 and ABT-737, but not ABT-199, were synergistic with carboplatin in cell growth assays and potentiated cell death when assessed by trypan blue staining. Furthermore, WEHI-539 and ABT-737 augmented carboplatin induced caspase 3/7 activity, PARP cleavage and annexin V labelling, but ABT-199 failed to do so. CONCLUSIONS: These observations suggest that compounds which target Bcl-X(L) are necessary if BH3 mimetics are to be successfully used to treat patients with ovarian cancer and this highlights the need to develop strategies to minimize thrombocytopenia induced by such compounds.
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spelling pubmed-48325202016-04-16 Antagonism of Bcl-X(L) is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells Abed, Mohammed Najim Abdullah, Marwan Ibrahim Richardson, Alan J Ovarian Res Research BACKGROUND: BH3 mimetics are a class of drugs that antagonize the Bcl-2 family of apoptosis inhibitors. We have previously shown that these compounds can potentiate the activity of carboplatin against several ovarian cancer cell lines. However, recent clinical studies have highlighted that BH3 mimetics which antagonise Bcl-X(L) are associated with significant thrombocytopenia. This has led to the development of ABT-199 which specifically inhibits Bcl-2. Unfortunately, Bcl-X(L) appears to be more frequently deregulated in ovarian cancer than Bcl-2. We therefore compared the ability of ABT-199, and the Bcl-X(L) selective compound WEHI-539, to potentiate the activity of carboplatin in ovarian cancer cell lines. METHODS: WEHI-539, ABT-737 and ABT-199 were tested in combination with carboplatin using a panel of 6 ovarian cancer cell lines. The activity of the drugs was evaluated using cell growth assays, staining with trypan bue and measurement of apoptosis by measuring caspase 3/7 activity, PARP cleavage and annexin-V/propidium iodide staining. RESULTS: We found that WEHI-539 and ABT-737, but not ABT-199, were synergistic with carboplatin in cell growth assays and potentiated cell death when assessed by trypan blue staining. Furthermore, WEHI-539 and ABT-737 augmented carboplatin induced caspase 3/7 activity, PARP cleavage and annexin V labelling, but ABT-199 failed to do so. CONCLUSIONS: These observations suggest that compounds which target Bcl-X(L) are necessary if BH3 mimetics are to be successfully used to treat patients with ovarian cancer and this highlights the need to develop strategies to minimize thrombocytopenia induced by such compounds. BioMed Central 2016-04-14 /pmc/articles/PMC4832520/ /pubmed/27080533 http://dx.doi.org/10.1186/s13048-016-0234-y Text en © Abed et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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
Abed, Mohammed Najim
Abdullah, Marwan Ibrahim
Richardson, Alan
Antagonism of Bcl-X(L) is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells
title Antagonism of Bcl-X(L) is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells
title_full Antagonism of Bcl-X(L) is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells
title_fullStr Antagonism of Bcl-X(L) is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells
title_full_unstemmed Antagonism of Bcl-X(L) is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells
title_short Antagonism of Bcl-X(L) is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells
title_sort antagonism of bcl-x(l) is necessary for synergy between carboplatin and bh3 mimetics in ovarian cancer cells
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832520/
https://www.ncbi.nlm.nih.gov/pubmed/27080533
http://dx.doi.org/10.1186/s13048-016-0234-y
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