Inhibition of Glutathione Peroxidase Mediates the Collateral Sensitivity of Multidrug-resistant Cells to Tiopronin
| Autor: | Andrés E. Dulcey, Lisa M. Miller Jenkins, Alexandra D.T. Kwit, Kyle R. Brimacombe, James P. Madigan, Gary L. Griffiths, Kristen M. Pluchino, Andrew S. Goldsborough, Michael M. Gottesman, Matthew D. Hall, Travis S. Marshall |
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| Rok vydání: | 2014 |
| Předmět: |
Programmed cell death
GPX1 Molecular Sequence Data Pharmacology Biochemistry Tandem Mass Spectrometry Cell Line Tumor medicine Humans Amino Acid Sequence Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Glutathione Peroxidase Thiomalates Reactive oxygen species Base Sequence Chemistry Glutathione peroxidase Tiopronin Cell Biology Drug Resistance Multiple Multiple drug resistance Oligodeoxyribonucleotides Mechanism of action Drug Resistance Neoplasm Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization Cancer cell Additions and Corrections medicine.symptom Reactive Oxygen Species medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 289:21473-21489 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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