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Inhibition of mitochondrial protein translation sensitizes melanoma cells to arsenic trioxide cytotoxicity via a reactive oxygen species dependent mechanism

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Abstract

Purpose

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 2,000 marketed drugs and naturally occurring compounds, a variety of antibiotic inhibitors of mitochondrial protein translation were identified.

Methods

The mechanism of action for the most effective agent identified, thiostrepton, was examined in a panel of melanoma cells. Effects of combinatorial ATO and thiostrepton treatment on cytotoxicity, apoptosis, mitochondrial protein content, and reactive oxygen species (ROS) were assessed.

Results

Thiostrepton (1 μM) sensitized three out of five melanoma cell lines to ATO-mediated growth inhibition. Treatment with thiostrepton resulted in reduced levels of the mitochondrial-encoded protein cytochrome oxidase I (COX1). Exposure to thiostrepton in combination with ATO resulted in increased levels of cleaved poly (ADP-ribose) polymerase and cellular ROS. The growth inhibitory and pro-apototic effects of addition of the ATO/thiostrepton combination were reversed by the free radical scavenger N-acetyl-l-cysteine.

Conculsions

Our data suggest that thiostrepton enhances the cytotoxic effects of ATO through a ROS-dependent mechanism. Co-administration of oxidative stress-inducing drugs such as thiostrepton in order to enhance the efficacy of ATO in the treatment of melanoma warrants further investigation.

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Acknowledgments

This work was supported by grants from the NIH (R21AR050645) and by a grant from Jacklyn and Miguel Bezos to SJO.

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Authors and Affiliations

  1. Department of Dermatology, NYU School of Medicine, TH-100, 560 First Avenue, New York, NY, 10016, USA

    Benjamin D. Bowling, Nicole Doudican, Prashiela Manga & Seth J. Orlow

  2. Yale University School of Medicine, New Haven, CT, USA

    Benjamin D. Bowling

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  1. Benjamin D. Bowling
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  2. Nicole Doudican
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  4. Seth J. Orlow
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Correspondence to Seth J. Orlow.

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Bowling, B.D., Doudican, N., Manga, P. et al. Inhibition of mitochondrial protein translation sensitizes melanoma cells to arsenic trioxide cytotoxicity via a reactive oxygen species dependent mechanism. Cancer Chemother Pharmacol 63, 37–43 (2008). https://doi.org/10.1007/s00280-008-0705-y

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  • DOI: https://doi.org/10.1007/s00280-008-0705-y

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