Jawad, Mohammed Jasim (2020) Translational studies to support the use of pitavastatin as a cancer therapeutic. Doctoral thesis, Keele University.

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Abstract

Ovarian cancer is the fifth leading cause of death associated with cancer. Initially, the disease responds to surgical cytoreduction, followed by chemotherapy. The primary response rate for chemotherapy is about 80%. Unfortunately, most patients relapse and tumours eventually become frontline therapy refractory. At this point, the lack of widely successful treatments contributes to a low 5-year survival. New therapeutic agents or therapy approaches are therefore required. Statins exert anticancer modality by cause cancer cell death by preventing the synthesis of geranylgeraniol an intermediate of mevalonate pathway. Moreover, we found that exogenous geranylgeraniol can suppress the pro-apoptotic activity of pitavastatin in vitro. Thus, suggesting that strict dietary regimen should be maintained to achieve correct pitavastatin therapeutic efficacy. Likewise, supplementation of diet with geranylgeraniol observed to suppress the pitavastatin-induced regression of ovarian cancer xenografts in mice. Several human foods have already been shown to contain geranylgeraniol. We tested 30 organic solvent foods extracts to see their ability to suppress anticancer activity of pitavastatin in vitro. The foods included eight oils, several types of solid foods and eleven fruits and vegetables. The IC50s of growth inhibition of pitavastatin were (5.2 μM, 8.2 μM) for Ovcar-4 and Fuov1 ovarian cancer cell line respectively. Pitavastatin anticancer activity is blocked completely by adding of geranylgeraniol or solvent extracts from sunflower oil. Some food extracts from lettuce, corn oil, ground nut oil, grape seed oil black bean and oats partially blocked the effect of pitavastatin, whereas the other foods did not. This research identified several foods apparently lack geranylgeraniol and which patients could eat while enrolled in clinical trials of pitavastatin.
Among the most effective and commonly used cancer treatment agents are natural and synthetic compounds that disrupt the dynamics of microtubules. However, there is still a lack of reliable markers that disrupt the dynamics of microtubules can decide the sensitivity of cancer cells to targeting agents of microtubules and play a role in tumour cell resistance to these agents. This growing family of microtubule-associated proteins (MAP) includes products from oncogenes' apoptosis regulators, suggesting that altering the dynamics of microtubules may be one of the critical events in tumour origin and tumour progression. The objective of this study is to integrate microtubule-targeting therapies and relevance with highlight MAP7-tubulin-pitavastatin interactions as a new avenue for isoprenoid-related activity to inhibit mevalonate production. We found highly express of MAP-7 in sensitive cells to pitavastatin (OVCAR-8 & OVSAHO) and the sensitivity is decreased after gene transfection of MAP-7 especially in OVSAHO cell line while no significant changes with KIF5-B on the sensitivity of cancer cells. Interestingly, we noticed a significant change in tubulin level after course time of treatment (24,48,72h) of ovarian cancer cell lines with single /double IC50 of pitavastatin. Consequently, we tried the CNP role in rescuing of mevalonate pathway which show significant change as well, based on the available evidence, we suggest that the isoprenoid (GGOH & FARNSOL) has important role in microtubules changes at its carboxyl-terminals but does not binding directly, CNP make association between isoprenoid and Cytoskeleton of cancer cell.
Repurposing statins for use in oncology is an attractive strategy, while legitimate concerns about the drug's potential for myopathy. In addition, certain pharmacological agents inhibiting the ovarian cancer cell therefore we evaluated causes of ovarian cancer cell death synergistically. To identify additional drugs that could interact synergistically with pitavastatin, it was identified ivermectin that potentiated pitavastatin activity and/or had notable activity as a single agent. In several cell growth and viability assays, this study confirmed the synergistic interaction between ivermectin and pitavastatin. These data suggest that inhibiting drug combinations can increase the pitavastatin therapeutic window and offer potential treatment for ovarian cancer.

Item Type: Thesis (Doctoral)
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Contributors: Richardson, A (Thesis advisor)
Depositing User: Lisa Bailey
Date Deposited: 16 Oct 2020 08:44
Last Modified: 16 Oct 2020 08:44
URI: https://eprints.keele.ac.uk/id/eprint/8739

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