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.
Highlights
Tiopronin is a small molecule that selectively kills multidrug-resistant cancer cells
Selective toxicity of tiopronin toward Multidrug resistance (MDR) cells is achieved by inhibition of glutathione peroxidase (GPx), and the mode of inhibition of GPx1 by tiopronin is shown in this report
The degree of collateral sensitivity is defined by a SR, which is calculated as the ratio of the IC50 of a compound for parental cells divided by its IC50 for MDR cells (in this case ((KB-3-1 IC50)/ (KB-V1 IC50))
Summary
Tiopronin is a small molecule that selectively kills multidrug-resistant cancer cells. The natural product austocystin D is more toxic to MDR cell lines because up-regulation of cytochrome P450s in MDR cells leads to increased activation of the drug [10], and cisplatin-resistant cells with down-regulated topoisomerase I expression show hypersensitivity to topoisomerase II inhibitors [11] These observations suggest that a range of known molecular alterations in MDR cells can be selectively targeted. Because tiopronin is a GPx inhibitor and given the view that ROS might play a role in the mechanism of action of other CS agents [4, 17], we hypothesized that some MDR cells may be collaterally sensitive to tiopronin via GPx inhibition, leading to ROS generation To examine this hypothesis, we assessed several tipronin analogs as GPx inhibitors and have shown selective toxicity toward MDR KB-V1 adenocarcinoma cells compared with the parent (drug-sensitive) KB-3-1 cell line. The generation of ROS in cells in the presence of tiopronin was examined by confocal microscopy (CellROX) and a quantitative plate-based assay (dihydrofluorescein diacetate) using dyes that fluoresce upon oxidation
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