Date of Award

12-17-2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Applied Science

First Advisor

nawab ali

Abstract

The agents that induce apoptosis in cancerous cells are considered as potential candidates for cancer therapy. Inositol polyphosphates, the naturally occurring compounds, regulate diverse cellular processes including induction of apoptosis in certain cancerous cells and hence can be considered as potential anticancer agents. The aim of this research dissertation was to establish firmly the role of inositol polyphosphates in induction of apoptosis by examining their mechanism of action. The overall hypothesis was that alterations in intracellular levels of inositol polyphosphates would bring about apoptotic changes. The hypothesis was tested by changing endogenous inositol polyphosphates by way of chemical treatments known to alter these compounds. First, effects of various inositol polyphosphates were examined by exogenous administration. Among inositol polyphosphates, inositol hexakis-phosphate was found to be the most potent inducer of apoptosis. Using a structural analog of inositol hexakisphosphate, these effects were proved to be specifically mediated by interaction of phosphate groups on the inositol ring and not due to a non-specific negative charge present on the inositol. Evidences indicate that not only does exogenously administered but also endogenously manipulated inositol polyphosphates alter apoptotic markers. Additionally, changes in cellular levels of inositol polyphosphates were investigated during apoptosis. Since cellular levels of inositol polyphosphates are regulated by multiple inositol polyphosphate phosphatase, an enzyme that metabolizes them, we have questioned whether the enzyme expression also changes during apoptosis. The expression of the protein, mRNA, and the enzyme activity of Minpp were increased during apoptosis suggesting that inositol polyphosphates are indeed one of the regulators of apoptosis and hence could be used as potential cancer therapeutic agents.

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