Date of Award

1-5-2009

Document Type

Thesis

Degree Name

Medical Doctor (MD)

First Advisor

David Leffell

Abstract

Inhibition of mitochondrial protein translation sensitizes melanoma cells to arsenic trioxide cytotoxicity via a reactive oxygen species dependent mechanism. Benjamin D. Bowling, Nicole Doudican, Prashiela Manga, and Seth J. Orlow, Department of Dermatology, NYU School of Medicine, New York City, New York. (Sponsored by David J. Leffell, Department of Dermatology, Yale University School of Medicine). Current standard chemotherapeutic regimens for malignant melanoma are unsatisfactory. Although in vitro studies of arsenic trioxide (ATO) have demonstrated promise against melanoma, recent phase II clinical trials have failed to show any significant clinical benefit when used as a single agent. To enhance the efficacy of ATO in the treatment of melanoma, we sought to identify compounds that potentiate the cytotoxic effects of ATO in melanoma cells. Through a screen of 2000 marketed drugs and naturally occurring compounds, and subsequent mechanistic testing, a variety of antibiotic inhibitors of mitochondrial protein translation were identified. The most effective of the agents identified, thiostrepton, significantly enhanced ATO-mediated cytotoxicity and apoptosis in a panel of melanoma cell lines. Treatment with thiostrepton resulted in reduced levels of the mitochondrial-encoded protein cytochrome oxidase I. Exposure to thiostrepton in combination with ATO resulted in a dramatic increase in cellular levels of reactive oxygen species (ROS). Furthermore, addition of the free radical scavenger N-acetyl-lcysteine (NAC) rescued cells from ATO/thiostrepton-mediated cytotoxicity. Our data suggest that thiostrepton enhances the cytotoxic effects of ATO through a ROSdependent mechanism. Co-administration of oxidative stress-inducing drugs such as thiostrepton in order to enhance the efficacy of ATO warrants further clinical investigation.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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