Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Clinical-Bioanalytical Chemistry

Department

Chemistry

First Advisor

Kalafatis, Michael

Subject Headings

Biochemistry

Abstract

The application of recombinant human Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (rhTRAIL) for the treatment of cancer holds great promise due to its ability to selectively induce apoptosis in cancer cells while not harming normal healthy cells. This is evident by the robust levels of apoptosis induced in malignant melanoma cells while no event of apoptosis was observed in the non-transformed counterpart of melanomas, melanocytes. However, the clinical utility of rhTRAIL is limited due to the heterogeneity seen in rhTRAIL-sensitivity among cancers. rhTRAIL-resistance is especially prevalent in cases of malignant melanoma. Melanoma rhTRAIL-resistance can be attributed to a number of different causations including low expression of rhTRAIL-binding receptors (death receptors (DRs)) and overexpression of anti-apoptotic proteins. Most noteworthy is the correlation between rhTRAIL-sensitivity and the membrane expression of rhTRAIL receptors DR4 and DR5. The membrane expression of DR4 and DR5 may be potential markers for predicting a patient’s sensitivity to rhTRAIL. We propose the development of an in vitro assay to measure the membrane expression of DR4 and DR5 to determine a patient’s suitability for rhTRAIL-treatment. Additionally, rhTRAIL-resistance can be circumvented by combining rhTRAIL with the “Mother Nature”-derived compound quercetin. Quercetin possesses the ability to modulate some of the cellular components that confer rhTRAIL-resistance. Resistant malignant melanomas are sensitized to the effects of rhTRAIL by the quercetin-mediated upregulation of DR4 and DR5 and the downregulation of the anti-apoptotic protein FLIP. Overall, these data show the potential of rhTRAIL to act as a potent anti-cancer therapeutic and methods to overcome rhTRAIL-resistance.

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