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A comparison of the cytotoxic effects of fatty acids on in vitro breast and prostate cell lines

Robinson, Glenn F. (2016) A comparison of the cytotoxic effects of fatty acids on in vitro breast and prostate cell lines. Doctoral thesis, University of Huddersfield.

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Abstract

Cancer is the leading cause of death worldwide and GLOBOCAN estimates that approximately 14.1 million new cases occurred in 2012 alone with approximately 8.2 million deaths attributed to cancer (Cancer Research UK 2015). Although chemotherapy can be an effective form of treatment for cancers, many drugs do not discriminate between rapidly dividing healthy cells and rapidly dividing cancer cells. Due to potential side effects such as nausea, fatigue and hair loss combined with emotional strain, patients often choose to suspend their treatment (Love et al. 1989). This in combination with issues related to resistance to some chemotherapy means there is an unmet clinical need for developing novel therapies with minimum side effects.

Lipids have been associated with a number of biological and pharmacological activites including anti-tumour activity of selected lipids. In particular omega-3 fatty acids have been strongly associated with anti-tumour properties (Iyengar et al. 2013; Brown et al. 2013). For example, the endocannabinoid 2-arachidonylglycerol (2-AG) is a structured lipid (C20:4ω6) which is a full agonist at CB1 and CB2 receptors, has been associated with anti-inflammatory, immunomodulatory, analgesic and anti-tumour properties (Hohmann 2011; Sugiura et al. 2002).

EPEA and DHEA, omega-3 fatty acid ethanolamides are formed endogenously from EPA and DHA which are pharmacologically and cyto-architecturally important, long chain, polyunsaturated fatty acids. EPEA and DHEA are known to have greater anti-proliferative potency than the free fatty acids EPA and DHA (Brown et al. 2010). The position of substituents on a glycerol backbone can affect the physical and pharmacological properties of glycerol esters and is of interest to understand the pharmacological relevance of regiospecific substitution of omega-3 fatty acids on the glycerol backbone.

This thesis describes a number of options to either chemically or chemoenzymatically produce regiospecific 1-monoglycerides from a number of fatty acid derivatives. The omega 3 monoglyceride derivatives 1-eicosapentaenoylglycerol and 1-docosahexaenoylglycerol were produced in greater than 97% purity and were tested for their cytotoxicity on MCF7 and PC3 in vitro cell lines. Regio-specifically synthesised shorter chain and less highly unsaturated PUFAs such as 1-linoleoylglycerol and 1-palmitoylglycerol were used as comparators in the MTT assay. 1-docosahexaenoylglycerol, the longest and most highly unsaturated chain tested, showed cytotoxic activity below 100 μM, affording IC50 values of
62.79 ± 5.39 μM and 59.05 ± 6.86 μM for MCF7 and PC3 cells respectively following 96 h exposure. Among other structured lipid tested the DHA diglyceride, didocosahexaenoin, a 1,3-diglyceride was the most cytotoxic with an IC50 of 3.82 ± 0.51 μM on PC3 cells following 96 h exposure. Didocosahexaenoin was shown to have a 3.26 (p = < 0.01) fold cytotoxic selectively for PC3 prostate carcinoma cells compared to that for PNT2 normal prostate cells. The mechanism of didocosahexaenoin’s-induced cell death in PC3 cells was determined to be via apoptosis and through the activation of caspase3/7. Didocosahexaenoin-treated PC3 cells were also seen to have a role in the production of intracellular reactive oxygen species which are likely to contribute to the induction of apoptosis.

In conclusion, DHA derivatives were the most effective fatty acid derivatives on PC3 and MCF7 cell lines with the sn-1,3-diglyceride form of DHA, didocosahexaenoin being the most potent lipid tested in terms of cytotoxicity to PC3 prostate carcinoma cells. The mechanism of action of didocosahexaenoin was studied and it was found to act by the induction of reactive oxygen species and apoptosis.

Item Type: Thesis (Doctoral)
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Schools: School of Applied Sciences
Depositing User: Sally Hughes
Date Deposited: 07 Feb 2017 16:48
Last Modified: 07 Feb 2017 18:39
URI: http://eprints.hud.ac.uk/id/eprint/31105

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