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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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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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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. |
format | Online Article Text |
id | pubmed-5556066 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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