Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer

Abstract Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a...

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Autores principales:	Elizabeth de Wolf, Marwan Ibrahim Abdullah, Stefanie M. Jones, Karen Menezes, Darren M. Moss, Falko P. Drijfhout, Sarah R. Hart, Clare Hoskins, Euan A. Stronach, Alan Richardson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ba16009471344089ac5a439986164551
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spelling	oai:doaj.org-article:ba16009471344089ac5a4399861645512021-12-02T12:32:27ZDietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer10.1038/s41598-017-05595-42045-2322https://doaj.org/article/ba16009471344089ac5a4399861645512017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05595-4https://doaj.org/toc/2045-2322Abstract Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary. Pitavastatin, the only statin with this profile, has not undergone clinical evaluation in oncology. The target of pitavastatin, hydroxymethylglutarate coenzyme-A reductase (HMGCR), was found to be over-expressed in all ovarian cancer cell lines examined and upregulated by mutated TP53, a gene commonly altered in ovarian cancer. Pitavastatin-induced apoptosis was blocked by geranylgeraniol and mevalonate, products of the HMGCR pathway, confirming that pitavastatin causes cell death through inhibition of HMGCR. Solvent extracts of human and mouse food were also able to block pitavastatin-induced apoptosis, suggesting diet might influence the outcome of clinical trials. When nude mice were maintained on a diet lacking geranylgeraniol, oral pitavastatin caused regression of Ovcar-4 tumour xenografts. However, when the animal diet was supplemented with geranylgeraniol, pitavastatin failed to prevent tumour growth. This suggests that a diet containing geranylgeraniol can limit the anti-tumour activity of pitavastatin and diet should be controlled in clinical trials of statins.Elizabeth de WolfMarwan Ibrahim AbdullahStefanie M. JonesKaren MenezesDarren M. MossFalko P. DrijfhoutSarah R. HartClare HoskinsEuan A. StronachAlan RichardsonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Elizabeth de Wolf Marwan Ibrahim Abdullah Stefanie M. Jones Karen Menezes Darren M. Moss Falko P. Drijfhout Sarah R. Hart Clare Hoskins Euan A. Stronach Alan Richardson Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer
description	Abstract Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary. Pitavastatin, the only statin with this profile, has not undergone clinical evaluation in oncology. The target of pitavastatin, hydroxymethylglutarate coenzyme-A reductase (HMGCR), was found to be over-expressed in all ovarian cancer cell lines examined and upregulated by mutated TP53, a gene commonly altered in ovarian cancer. Pitavastatin-induced apoptosis was blocked by geranylgeraniol and mevalonate, products of the HMGCR pathway, confirming that pitavastatin causes cell death through inhibition of HMGCR. Solvent extracts of human and mouse food were also able to block pitavastatin-induced apoptosis, suggesting diet might influence the outcome of clinical trials. When nude mice were maintained on a diet lacking geranylgeraniol, oral pitavastatin caused regression of Ovcar-4 tumour xenografts. However, when the animal diet was supplemented with geranylgeraniol, pitavastatin failed to prevent tumour growth. This suggests that a diet containing geranylgeraniol can limit the anti-tumour activity of pitavastatin and diet should be controlled in clinical trials of statins.
format	article
author	Elizabeth de Wolf Marwan Ibrahim Abdullah Stefanie M. Jones Karen Menezes Darren M. Moss Falko P. Drijfhout Sarah R. Hart Clare Hoskins Euan A. Stronach Alan Richardson
author_facet	Elizabeth de Wolf Marwan Ibrahim Abdullah Stefanie M. Jones Karen Menezes Darren M. Moss Falko P. Drijfhout Sarah R. Hart Clare Hoskins Euan A. Stronach Alan Richardson
author_sort	Elizabeth de Wolf
title	Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer
title_short	Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer
title_full	Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer
title_fullStr	Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer
title_full_unstemmed	Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer
title_sort	dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ba16009471344089ac5a439986164551
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Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer

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