Date of Award

Spring 2012

Document Type

Thesis

Department

Life & Environmental Sciences

First Advisor

John Addis

Second Advisor

Daniel Gretch

Third Advisor

Brandon Sheafor

Abstract

Multidrug resistance (MDR) has become a major obstacle to chemotherapeutic cancer treatments. MDR is often a result of an up-regulation and overproduction of an ATP-binding cassette (ABC) transporter following chemotherapy. The phenomenon called collateral sensitivity (CS) is associated with MDR cancers and alleviates this condition in vitro. CS agents selectively kill MDR cancer cells over non-MDR cancer cells, often by up-regulating the overproduced ABC transporters. A common ABC transporter that is over-expressed in MDR cancer cells is P-glycoprotein, P-gp. The orphan drug tiopronin has been previously shown to mediate CS in a non-P-gp dependent manner. This means that the CS of tiopronin may be due to another ABC transporter or possibly not from an ABC transporter at all. I attempted to understand the mechanism of tiopronin’s CS capabilities and found that reactive oxygen species (ROS) playa major role in tiopronin-mediated CS. Specifically, superoxide (O2) as little effect on the CS of tiopronin while hydrogen peroxide (H2O2) affects tiopronin-mediated CS. However, H2O2 cannot induce CS by itself, indicating that H2O2 is likely an intermediate necessary for tiopronin’s CS capability but is not the direct cause of CS. Further research should be conducted to investigate the mechanism for tiopronin-mediated CS.

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