Date of Award

6-1-2014

Document Type

Thesis - SCU Access Only

Publisher

Santa Clara University

First Advisor

Zhiwen Zhang

Abstract

The objective of our project was to sensitize drug-resistant cancer cells to conventional forms of chemotherapy, in particular taxane drugs which stabilize tubulin, thereby arresting dividing cells in mitosis, thus activating the apoptotic pathway in these cells and driving them to their death. One mechanism that allows cells to acquire resistance is the overexpression of a certain class of proteins called inhibitors of apoptosis (IAPs). Upregulation of these molecules permits the cells to evade death, despite their having incurred damaged from exposure to toxic levels of taxane. We employed a cloaking agent (a molecular formulation provided to us by our pharma-collaborator Novartis) that was developed to block the action of these IAPs by binding them and prompting them to disengage the cells' repressed caspase “executioner” proteases. This in turn causes apoptosis to resume, with the downstream effect being an overall sensitization to taxane. To substantiate this hypothesis, we performed a number of proof-of-concept experiments that included several rounds of cell viability assays. In the first step, we treated a parental strain and a drug-resistant variant with taxane alone to determine the IC50 values of the two cell lines and to characterize the difference in their resistance levels. In the second step, we subjected both cell lines to the cloaking agent by itself to confirm that it is not detrimental to the cells in the absence of taxane. In the third step, we quantified cell survival rates upon combination treatment with taxane and inhibitor together and found that there was an increase in cell death with increasing concentrations of inhibitor (i.e. we successfully lowered the IC50 values). The implication of our findings is the possibility of a novel treatment regimen that clinicians can use to try and kill robust cancer cells that have acquired resistance after repeated rounds of chemotherapy. The treatment could only be implemented in human patients following in vivo studies and clinical trials.

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