Robinson, Elizabeth (2015) The preclinical evaluation of simvastatin and pitavastatin for the treatment of ovarian cancer. Doctoral thesis, Keele University.

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Abstract

Ovarian cancer is the fifth most common cancer which affects women in the United Kingdom. The 5-year survival rate is less than 45% despite improvements in chemotherapeutic regimens. Platinum-based therapy in combination with other chemotherapy including paclitaxel is currently the best standard of care for ovarian cancer. However, many women relapse with drug-resistant disease and this has led to the development of alternative drug therapies. This research evaluated two statins, simvastatin and pitavastatin, in several ovarian cancer models. Statins competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in the mevalonate pathway, resulting in the cellular depletion of the isoprenoid, geranylgeranyl diphosphate, and a reduction in the prenylation and localisation of many proteins including Ras, Rho and Rab involved in cell signalling. This is likely to have contributed to the decrease in cell proliferation, induction of apoptosis, and simultaneous induction and inhibition of autophagy
observed when ovarian cancer cells were exposed to statins, although the mechanisms remain poorly defined. The concentration of statins required to cause cell death in ovarian cancer cells was significantly higher than that achieved in patients receiving a standard 40 mg dose for hypercholesterolaemia. Continual inhibition of HMGCR for several days was necessary to induce cell death. Lipids consumed in the diet may reverse the cytotoxic effects of the statins, suggesting that patients receiving statins for cancer therapy may require dietary modification. Studies evaluating statins in combination with carboplatin or targeted therapeutics demonstrated limited synergy, and in some cases, profound antagonism, and therefore, statins may be best evaluated as single agents. Statins retained cytotoxic activity in ovarian cancer cells resistant to chemotherapy, supporting the use of statins in chemoresistant disease. These observations will help to inform the design of future clinical trials evaluating statins in
ovarian cancer.

Item Type: Thesis (Doctoral)
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Depositing User: Lisa Bailey
Date Deposited: 25 Oct 2016 08:56
Last Modified: 25 Oct 2016 08:56
URI: http://eprints.keele.ac.uk/id/eprint/2345

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