title: Inhibition of glutathione peroxidase mediates the collateral sensitivity of multidrug-resistant cells to tiopronin.
abstract: 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.
authors.affiliation: From the Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
authors.affiliation: From the Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Travis S
authors.initials: TS
authors.lastname: Marshall
authors.affiliation: From the Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Alexandra D T
authors.initials: AD
authors.lastname: Kwit
authors.affiliation: From the Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Miller Jenkins
authors.affiliation: the Imaging Probe Development Center, NHLBI, National Institutes of Health, Rockville, Maryland 20850.
authors.forename: Andrés E
authors.initials: AE
authors.lastname: Dulcey
authors.affiliation: From the Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: James P
authors.initials: JP
authors.lastname: Madigan
authors.affiliation: From the Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Pluchino
authors.affiliation: From the Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Goldsborough
authors.affiliation: From the Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Brimacombe
authors.affiliation: the Imaging Probe Development Center, NHLBI, National Institutes of Health, Rockville, Maryland 20850.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Griffiths
authors.affiliation: From the Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and mgottesman@nih.gov.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D017382:Reactive Oxygen Species / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053719:Tandem Mass Spectrometry; D013870:Thiomalates / Q000494:pharmacology; D008625:Tiopronin / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D009838:Oligodeoxyribonucleotides; D017382:Reactive Oxygen Species; D013870:Thiomalates; C046062:2-thiomalic acid; D008625:Tiopronin; D005979:Glutathione Peroxidase
keywords: Cell Death; Chemoresistance; Enzyme Inhibitor; Glutathione Peroxidase; Oxygen Radicals; Reactive Oxygen Species (ROS)