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Relationship between multidrug resistance, hypersensitivity to resistance modifiers and cell volume in Chinese
S E Vickers1, M W Stow, J R Warr
1Biology Department, University of York, Heslington, U.K.
Abstract:
We have previously shown that very high levels of hypersensitivity to several resistance modifiers are correlated with increasing multidrug resistance in a series of Chinese hamster ovary cell lines. We have now selected a new member of the series which is an exception to this correlation in that although it is almost twice as multidrug resistant as the cell line from which it was derived, it shows much less hypersensitivity to resistance modifiers. Level of resistance modifier hypersensitivity correlated with the level of reduction of verapamil accumulation in these cells, and with the density of P-glycoprotein, but since the selection of this cell line has involved a doubling of cell volume, it was not correlated with total amount of P-glycoprotein.
Insights
Multidrug resistance in cancer cells can vary. A new cell line shows high resistance but reduced hypersensitivity to modifiers, challenging previous correlations with P-glycoprotein density.
Area of Science:
- Cell Biology
- Pharmacology
- Biochemistry
Background:
- Previous studies linked high hypersensitivity to resistance modifiers with increased multidrug resistance (MDR) in Chinese hamster ovary (CHO) cell lines.
- This established a correlation between modifier sensitivity and MDR levels.
Purpose of the Study:
- To investigate a newly selected CHO cell line that presents an exception to the previously observed correlation between hypersensitivity to resistance modifiers and MDR.
- To explore the relationship between cell volume, P-glycoprotein (P-gp) expression, and drug accumulation in this exceptional cell line.
Main Methods:
- Selection and characterization of a new Chinese hamster ovary (CHO) cell line with altered drug resistance and modifier sensitivity profiles.
- Quantification of multidrug resistance (MDR) levels.
- Assessment of hypersensitivity to resistance modifiers.
- Measurement of verapamil accumulation within cells.
- Determination of P-glycoprotein (P-gp) density and total amount, considering cell volume.
Main Results:
- The new cell line exhibited nearly double the multidrug resistance (MDR) of its parent line.
- Despite increased MDR, the new cell line showed significantly reduced hypersensitivity to resistance modifiers.
- Hypersensitivity to resistance modifiers correlated with reduced verapamil accumulation and P-glycoprotein (P-gp) density.
- The correlation between hypersensitivity and P-gp was not observed with the total amount of P-gp due to a doubling of cell volume in the selected line.
Conclusions:
- The study identified a novel exception to the established correlation between resistance modifier hypersensitivity and multidrug resistance (MDR) in CHO cells.
- Reduced hypersensitivity in this cell line is linked to altered P-glycoprotein (P-gp) expression dynamics, particularly P-gp density rather than total amount, influenced by cell volume changes.
- Findings suggest a more complex relationship between P-gp, cell physiology, and drug resistance than previously understood.