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Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells

Only 40% of patients with advanced ovarian cancer survive more than 5 years. We have previously shown that pitavastatin induces regression of ovarian cancer xenografts in mice. To evaluate whether the response of ovarian cancer cells to pitavastatin is potentiated by farnesyl diphosphate synthase in...

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Autores principales: Abdullah, Marwan Ibrahim, Abed, Mohammed Najim, Richardson, Alan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556066/
https://www.ncbi.nlm.nih.gov/pubmed/28808351
http://dx.doi.org/10.1038/s41598-017-08649-9
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author Abdullah, Marwan Ibrahim
Abed, Mohammed Najim
Richardson, Alan
author_facet Abdullah, Marwan Ibrahim
Abed, Mohammed Najim
Richardson, Alan
author_sort Abdullah, Marwan Ibrahim
collection PubMed
description Only 40% of patients with advanced ovarian cancer survive more than 5 years. We have previously shown that pitavastatin induces regression of ovarian cancer xenografts in mice. To evaluate whether the response of ovarian cancer cells to pitavastatin is potentiated by farnesyl diphosphate synthase inhibitors or geranylgeraniol transferase I inhibitors, we evaluated combinations of pitavastatin with zoledronic acid, risedronate and GGTI-2133 in a panel of ovarian cancer cells. Pitavastatin (IC(50) = 0.6–14 μM), zoledronic acid (IC(50) = 21–57 μM), risedronate (IC(50) > 100 μM) or GGTI-2133 (IC(50) > 25 μM) inhibited the growth of ovarian cancer cell cultures. Combinations of pitavastatin with zoledronic acid displayed additive or synergistic effects in cell growth assays in 10 of 11 cell lines evaluated as well as in trypan blue exclusion, cellular ATP or caspase 3/7, 8 and 9 assays. Pitavastatin reduced levels of GGT-IIβ and the membrane localization of several small GTPases and this was potentiated by zoledronic acid. siRNA to GGT-Iβ and GGT-IIβ used in combination, but not when used individually, significantly increased the sensitivity of cells to pitavastatin. These data suggest that zoledronic acid, a drug already in clinical use, may be usefully combined with pitavastatin in the treatment of ovarian cancer.
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spelling pubmed-55560662017-08-16 Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells Abdullah, Marwan Ibrahim Abed, Mohammed Najim Richardson, Alan Sci Rep Article Only 40% of patients with advanced ovarian cancer survive more than 5 years. We have previously shown that pitavastatin induces regression of ovarian cancer xenografts in mice. To evaluate whether the response of ovarian cancer cells to pitavastatin is potentiated by farnesyl diphosphate synthase inhibitors or geranylgeraniol transferase I inhibitors, we evaluated combinations of pitavastatin with zoledronic acid, risedronate and GGTI-2133 in a panel of ovarian cancer cells. Pitavastatin (IC(50) = 0.6–14 μM), zoledronic acid (IC(50) = 21–57 μM), risedronate (IC(50) > 100 μM) or GGTI-2133 (IC(50) > 25 μM) inhibited the growth of ovarian cancer cell cultures. Combinations of pitavastatin with zoledronic acid displayed additive or synergistic effects in cell growth assays in 10 of 11 cell lines evaluated as well as in trypan blue exclusion, cellular ATP or caspase 3/7, 8 and 9 assays. Pitavastatin reduced levels of GGT-IIβ and the membrane localization of several small GTPases and this was potentiated by zoledronic acid. siRNA to GGT-Iβ and GGT-IIβ used in combination, but not when used individually, significantly increased the sensitivity of cells to pitavastatin. These data suggest that zoledronic acid, a drug already in clinical use, may be usefully combined with pitavastatin in the treatment of ovarian cancer. Nature Publishing Group UK 2017-08-14 /pmc/articles/PMC5556066/ /pubmed/28808351 http://dx.doi.org/10.1038/s41598-017-08649-9 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Abdullah, Marwan Ibrahim
Abed, Mohammed Najim
Richardson, Alan
Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells
title Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells
title_full Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells
title_fullStr Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells
title_full_unstemmed Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells
title_short Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells
title_sort inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556066/
https://www.ncbi.nlm.nih.gov/pubmed/28808351
http://dx.doi.org/10.1038/s41598-017-08649-9
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