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Multidrug-resistance phenotype in Chinese hamster ovary cells
Abstract:
Multidrug resistance is a complex pleiotropic phenotype of cross-resistance and collateral sensitivity to unrelated compounds observed in many mammalian cell mutants selected for resistance to single agents. In Chinese hamster ovary cells, colchicine-resistant mutants expressing this phenotype have been characterized extensively. Such mutants arise apparently from a single genetic event, and the basis of this phenotype appears to be localized at the membrane level, resulting in altered drug permeability. Expression of a 170,000-dalton surface glycoprotein (P-glycoprotein) has been identified to correlate with the multidrug-resistance phenotype. Selection of a second mutation in colchicine-resistant mutants, for resistance to phytohemagglutinin, results in an alteration of the carbohydrate moiety in P-glycoprotein and other surface components. This mutation does not noticeably affect the multi-drug-resistance phenotype. The altered permeability of mutant cells to drugs, however, can be modulated by nonionic detergents or metabolic inhibitors. These findings are consistent with a molecular mechanism of multidrug resistance whereby the pleiotropic response of the cell is mediated by an overexpression of a cell-surface protein, the P-glycoprotein.
Insights
Multidrug resistance in cells involves altered drug permeability, often linked to P-glycoprotein. This cell surface protein
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Multidrug resistance (MDR) is a complex phenotype observed in mammalian cells selected for resistance to single agents.
- This phenotype involves cross-resistance and collateral sensitivity to unrelated compounds.
- Chinese hamster ovary (CHO) cells resistant to colchicine exhibit this MDR phenotype.
Purpose of the Study:
- To investigate the molecular basis of multidrug resistance in mammalian cells.
- To characterize the role of cell surface glycoproteins in the MDR phenotype.
- To explore the modulation of drug permeability in resistant cell mutants.
Main Methods:
- Selection of colchicine-resistant mutants in CHO cells.
- Characterization of phenotypic alterations at the membrane level.
- Identification and analysis of cell surface glycoproteins, including P-glycoprotein.
- Introduction of a second mutation for phytohemagglutinin resistance.
- Assessment of drug permeability modulation by nonionic detergents and metabolic inhibitors.
Main Results:
- Colchicine-resistant mutants exhibit altered drug permeability.
- Expression of a 170,000-dalton surface glycoprotein (P-glycoprotein) correlates with the MDR phenotype.
- A second mutation affecting P-glycoprotein's carbohydrate moiety did not alter the MDR phenotype.
- Altered drug permeability in mutant cells can be modulated by external agents.
Conclusions:
- The MDR phenotype in these mutants is likely mediated by an altered cell membrane.
- Overexpression of P-glycoprotein is a key molecular mechanism underlying pleiotropic multidrug resistance.
- Drug permeability is a targetable aspect of MDR that can be modulated.