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

Abstract 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 sy...

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Autores principales:	Marwan Ibrahim Abdullah, Mohammed Najim Abed, Alan Richardson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8ca55e1241a04e7ca10cbcd71758b463
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spelling	oai:doaj.org-article:8ca55e1241a04e7ca10cbcd71758b4632021-12-02T12:31:59ZInhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells10.1038/s41598-017-08649-92045-2322https://doaj.org/article/8ca55e1241a04e7ca10cbcd71758b4632017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08649-9https://doaj.org/toc/2045-2322Abstract 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 (IC50 = 0.6–14 μM), zoledronic acid (IC50 = 21–57 μM), risedronate (IC50 > 100 μM) or GGTI-2133 (IC50 > 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.Marwan Ibrahim AbdullahMohammed Najim AbedAlan RichardsonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marwan Ibrahim Abdullah Mohammed Najim Abed Alan Richardson Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells
description	Abstract 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 (IC50 = 0.6–14 μM), zoledronic acid (IC50 = 21–57 μM), risedronate (IC50 > 100 μM) or GGTI-2133 (IC50 > 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	article
author	Marwan Ibrahim Abdullah Mohammed Najim Abed Alan Richardson
author_facet	Marwan Ibrahim Abdullah Mohammed Najim Abed Alan Richardson
author_sort	Marwan Ibrahim Abdullah
title	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_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_sort	inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8ca55e1241a04e7ca10cbcd71758b463
work_keys_str_mv	AT marwanibrahimabdullah inhibitionofthemevalonatepathwayaugmentstheactivityofpitavastatinagainstovariancancercells AT mohammednajimabed inhibitionofthemevalonatepathwayaugmentstheactivityofpitavastatinagainstovariancancercells AT alanrichardson inhibitionofthemevalonatepathwayaugmentstheactivityofpitavastatinagainstovariancancercells
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Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells

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