Inhibition of Glutathione Peroxidase Mediates the Collateral Sensitivity of Multidrug-resistant Cells to Tiopronin

• Published in: The Journal of biological chemistry 2014-08, Vol.289 (31), p.21473-21489
• Main Authors: Hall, Matthew D., Marshall, Travis S., Kwit, Alexandra D.T., Miller Jenkins, Lisa M., Dulcey, Andrés E., Madigan, James P., Pluchino, Kristen M., Goldsborough, Andrew S., Brimacombe, Kyle R., Griffiths, Gary L., Gottesman, Michael M.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Base Sequence; Cell Biology; Cell Death; Cell Line, Tumor; Chemoresistance; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme Inhibitor; Enzyme Inhibitors - pharmacology; Glutathione Peroxidase; Glutathione Peroxidase - antagonists & inhibitors; Glutathione Peroxidase - chemistry; Humans; Molecular Sequence Data; Oligodeoxyribonucleotides; Oxygen Radicals; Reactive Oxygen Species (ROS); Reactive Oxygen Species - metabolism; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry; Thiomalates - pharmacology; Tiopronin - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.581702

Multidrug resistance (MDR) is a major obstacle to the successful chemotherapy of cancer. MDR is often the result of overexpression of ATP-binding cassette transporters following chemotherapy. A common ATP-binding cassette transporter that is overexpressed in MDR cancer cells is P-glycoprotein, which actively effluxes drugs against a concentration gradient, producing an MDR phenotype. Collateral sensitivity (CS), a phenomenon of drug hypersensitivity, is defined as the ability of certain compounds to selectively target MDR cells, but not the drug-sensitive parent cells from which they were derived. The drug tiopronin has been previously shown to elicit CS. However, unlike other CS agents, the mechanism of action was not dependent on the expression of P-glycoprotein in MDR cells. We have determined that the CS activity of tiopronin is mediated by the generation of reactive oxygen species (ROS) and that CS can be reversed by a variety of ROS-scavenging compounds. Specifically, selective toxicity of tiopronin toward MDR cells is achieved by inhibition of glutathione peroxidase (GPx), and the mode of inhibition of GPx1 by tiopronin is shown in this report. Why MDR cells are particularly sensitive to ROS is discussed, as is the difficulty in exploiting this hypersensitivity to tiopronin in the clinic. Background: Tiopronin is a small molecule that selectively kills multidrug-resistant cancer cells. Results: Inhibition of glutathione peroxidase by tiopronin leads to elevated reactive oxygen species in MDR cells. Conclusion: Tiopronin mediates the killing of MDR cells by inhibition of glutathione peroxidases. Significance: Glutathione peroxidase inhibition may be a viable strategy for modulation of multidrug resistance in cancer.