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

de Wolf, Elizabeth; Abdullah, Marwan Ibrahim; Jones, Stefanie M; Menezes, Karen; Moss, Darren M; Drijfhout, Falko; Hart, Sarah; Hoskins, Clare; Stronach, Euan A; Richardson, A

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


Authors

Elizabeth de Wolf

Marwan Ibrahim Abdullah

Stefanie M Jones

Karen Menezes

Darren M Moss

Clare Hoskins

Euan A Stronach



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.

Acceptance Date Jun 5, 2017
Publication Date Jul 14, 2017
Journal Scientific Reports
Print ISSN 2045-2322
Publisher Nature Publishing Group
DOI https://doi.org/10.1038/s41598-017-05595-4
Publisher URL https://doi.org/10.1038/s41598-017-05595-4

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