School of Molecular & Cell Biology (ETDs)

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Start date: 2015End date: 2019

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    Investigating 2-hydroxypropyl-β-cyclodextrin (HPβCD) as a novel therapeutic agent for breast cancer
    (University of the Witwatersrand, Johannesburg, 2019) Saha, Sourav Taru; Kaur, Mandeep
    Cancer cells have an increased need for cholesterol, which is required for cell membrane integrity. Cholesterol accumulation has been described in various malignancies including breast cancer. Cholesterol has also been known to be the precursor of estrogen and vitamin D, both of which play a key role in the histology of breast cancer. Elevated cholesterol levels have been linked to breast cancer therefore depleting cholesterol levels in cancer cells can be a viable strategy for treatment. 2-hydroxypropyl-β-cyclodextrin (HPβCD) is a cholesterol depleting compound which is a cyclic amylose oligomer composed of glucose units. It solubilizes cholesterol and is proven to be toxicologically benign in humans. This led us to hypothesise that it might deplete cholesterol from cancer cells and may prove to be a clinically useful compound. Our work provides experimental evidences to support this hypothesis. We identified the potency of HPβCD in vitro against two breast cancer cell lines: MCF7 (Estrogen positive, ER+), MDA-MB-231 [Triple negative breast cancer (TNBC)], and compared the results against two normal cell lines: MRC-5 (Normal Human Lung Fibroblasts) and HEK-293 (Human embryonic kidney) using cytotoxic, apoptosis and cholesterol based assays. HPβCD treatment reduced intracellular cholesterol resulting in significant breast cancer cell growth inhibition through apoptosis. The results hold true for both ER+ and TNBC. We have also tested HPβCD in vivo in MF-1 mice xenograft model and obtained 73.9%, 94% and 100% reduction in tumour size for late, intermediate and early stage TNBC. These data suggest that HPβCD can prevent cholesterol accumulation in breast cancer cells and is a promising anti- cancer agent
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    Control of serine dehydratase activity in rat liver
    (University of the Witwatersrand, Johannesburg, 2015-02-24) Abed, Suliman; Manchester, K.L.
    Gluconeogenesis from amino acids in the liver is enhanced when the utilisation of glucose is limited under various hormonal and dietary conditions, such as diabetes, starvation or administration of a carbohydrate free diet. Pyruvate is of great importance as a carbon source for gluconeogenesis, since the sequence of gluconeogenic reaction is initiated by carboxylation of pyruvate to oxaloacetate. From this point of view, an important physiological role is suggested for serine dehydratase, which catalyses the degradation of serine to pyruvate and ammonia. The relationship of serine dehydratase levels to gluconeogenic activities, however, is poorly understood, A study of the hormonal and dietary control of serine dehydratase activity was carried out in vivo and in vitro in rat liver. Serine dehydratase was assayed by the colorimetric method of Suda and Nakagawa (1971) and the enzymatic method of Wimhurst and Manchester (1973). Both these methods have been found to be suitable since they are in agreement with each other and also give results which compare favourably with other published values. Activities of serine dehydratase from fresh liver and in slices of liver cultured for various periods have been compared. Also a study of the activity of another soluble enzyme, lactic dehydrogenase, was undertaken and the in vivo and in vitro levels were compared.