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Daunorubicin-resistant Chinese hamster ovary cells expressing multidrug resistance and a cell-surface P-glycoprotein
Abstract:
Independent lines of Chinese hamster ovary cells resistant to the antineoplastic drug, daunorubicin, were obtained by clonal isolation in increasing drug concentrations. A single daunorubicin-resistant phenotype typified by reduced cellular drug accumulation was observed. These mutants displayed a complex phenotype of resistance to a variety of unrelated drugs. Such properties are similar to those of membrane-altered colchicine-resistant lines (V. Ling and L.H. Thompson, J. Cell. Physiol., 83: 103-116, 1974). Analysis of the plasma membrane components of the daunorubicin-resistant clones by gel electrophoresis revealed a prominent cell surface glycoprotein with a molecular weight of about 170,000. This component was immunologically cross-reactive with the cell surface P-glycoprotein of about the same molecular weight, previously identified in colchicine-resistant cells. Thus, it appears that the mechanism of resistance characterized by P-glycoprotein expression could be the basis of many drug-resistant phenotypes.
Insights
Chinese hamster ovary cells developed resistance to daunorubicin, exhibiting cross-resistance to other drugs. This resistance is linked to a P-glycoprotein on the cell surface, suggesting a common mechanism for multidrug resistance.
Area of Science:
- Cell Biology
- Molecular Biology
- Pharmacology
Background:
- Drug resistance in cancer therapy is a significant challenge.
- Understanding the molecular mechanisms of multidrug resistance (MDR) is crucial for developing effective treatments.
- Previous studies identified P-glycoprotein in colchicine-resistant cells.
Purpose of the Study:
- To investigate the mechanism of daunorubicin resistance in Chinese hamster ovary (CHO) cells.
- To determine if daunorubicin resistance shares similarities with other drug-resistant phenotypes.
- To identify potential molecular markers associated with multidrug resistance.
Main Methods:
- Generating daunorubicin-resistant CHO cell lines through clonal isolation.
- Phenotypic characterization of drug resistance profiles.
- Analysis of plasma membrane proteins using gel electrophoresis.
- Immunological cross-reactivity studies using antibodies against P-glycoprotein.
Main Results:
- Daunorubicin-resistant CHO cell lines were successfully established.
- A single resistant phenotype was observed, characterized by reduced cellular drug accumulation.
- These mutants displayed cross-resistance to various unrelated drugs.
- A prominent cell surface glycoprotein (approx. 170,000 MW) was identified in resistant clones.
- This glycoprotein was immunologically similar to P-glycoprotein found in colchicine-resistant cells.
Conclusions:
- Daunorubicin resistance in CHO cells is associated with reduced drug accumulation.
- The observed cross-resistance suggests a common MDR mechanism.
- P-glycoprotein expression is likely a key factor in this drug resistance phenotype.
- This finding implies that P-glycoprotein-mediated resistance may underlie various drug-resistant phenotypes.