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

de Wolf, Elizabeth and Abdullah, Marwan and Jones, Stephanie M. and Menezes, Karen and Moss, Darren and Drijfhout, Falko P. and Hart, Sarah R. and Hoskins, Clare and Stronach, Euan A. and Richardson, Alan (2017) Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug resistant ovarian cancer. Scientific Reports, 7. 5410. ISSN 2045-2322 (https://doi.org/10.1038/s41598-017-05595-4)

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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.

ORCID iDs

de Wolf, Elizabeth, Abdullah, Marwan, Jones, Stephanie M., Menezes, Karen, Moss, Darren, Drijfhout, Falko P., Hart, Sarah R., Hoskins, Clare ORCID logoORCID: https://orcid.org/0000-0002-7200-0566, Stronach, Euan A. and Richardson, Alan;
  • Item type:Article
    ID code:70529
    Dates:
    Date
    Event
    14 July 2017
    Published
    5 June 2017
    Accepted
    Subjects:Medicine
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:14 Nov 2019 16:44
    Last modified:05 Nov 2024 22:03
    URI:https://strathprints.strath.ac.uk/id/eprint/70529
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