de Wolf, E, Abdullah, MI, Jones, SM, Menezes, K, Moss, DM, Drijfhout, FP ORCID: 0000-0002-3210-8038, Hart, S, Hoskins, C ORCID: 0000-0002-7200-0566, Stronach, EA and Richardson, A ORCID: 0000-0003-1825-3375 (2017) Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer. Scientific Reports, 7 (1). ISSN 2045-2322

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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.

Item Type: Article
Additional Information: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via Nature Publishing Group at https://doi.org/10.1038/s41598-017-05595-4 Please refer to any applicable terms of use of the publisher.
Subjects: R Medicine > R Medicine (General)
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Depositing User: Symplectic
Date Deposited: 19 Jul 2017 13:49
Last Modified: 23 Aug 2018 14:24
URI: http://eprints.keele.ac.uk/id/eprint/3762

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