Impact of Lipid Based Anticancer Drugs on Biomimetic Lipid Models and Eukaryotic Membranes
Abstract
Synthetic anti-tumour lipids are a class of drugs derived from lysophosphatidylcholine that are both cytotoxic and cytostatic and exert these effects preferentially on tumour cells compared to healthy tissues. Additionally, unlike most conventional chemotherapeutics, which target DNA, these drugs are membrane active and therefore non – mutagenic. These properties reduce both the amount and severity of side effects, improving the therapy for patients. While the mode of action has not been fully elucidated, it is believed that these drugs accumulate preferentially in rigid lipid domains leading to breakdown of these membrane structures. These domains are important sites for signal transduction and membrane trafficking and their disruption impacts cellular functions at various levels. Thus, the goal of this thesis was to use biophysical techniques to better characterize the properties and mode of action of three representative drugs: edelfosine, miltefosine and perifosine. Membrane extracts of Saccharomyces cerevisiae (budding yeast) cells treated with these drugs were spread as monolayers and characterized by surface pressure – area isotherms and Brewster angle microscopy. Edelfosine and miltefosine caused a breakdown of lateral domain organization, while perifosine did not. Additionally, the effect of the drugs on monolayers of diacylglycerol (which was found to sensitize cells to the drugs) and phosphatidic acid (which was found to be protective) were characterized similarly. These results showed that edelfosine and miltefosine stabilized both lipids, while perifosine destabilized diacylglycerol. Differential scanning calorimetry results also showed that phosphatidic acid had a protective effect against destabilization of the bilayers by the drugs. Finally, an assay using the fluorescent dye laurdan demonstrated that the different drugs induced different levels of fluidization on membranes based on the proportion of cholesterol and sphingomyelin. Overall these drugs were shown to have different interactions with different lipid classes, which contribute to a better understanding of their mode of action.
Description
Keywords
Biology--Molecular, Biophysics--Medical, Biochemistry
Citation
Mahadeo, M. (2017). Impact of Lipid Based Anticancer Drugs on Biomimetic Lipid Models and Eukaryotic Membranes (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26461