Resistance modulation in CHO cells by R-verapamil and bile salts is associated with physical and chemical changes in the cell membrane

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Abstract
Changes in multidrug resistance by resistance modifiers such as R-verapamil cause changes in fluidity of the cell membrane. The extent to which these changes involve structural alterations in membrane lipids has been investigated in CHO cells. Sensitive (AUXB1) and resistant (CH(R)C5) chinese hamster ovary cells (CHO) were grown in culture. Incubations were carried out with R-verapamil (0-10 microM) or the membrane perturbing agents tauro-cheno-deoxycholate (0-1.6 mM, TCDC) and tauro-urso-deoxycholate (0-3.5mM, TUDC). Cell membrane fluidity was determined by electron-paramagnetic resonance spectroscopy and membrane lipids by HPLC and TLC. The resistant CH(R)C5 subline had a higher cell membrane order (lower fluidity, S = 0.7234) in the interface region of the cell membrane than sensitive AUXB1 cells (S = 0.6984) determined using EPR. The MDR-modulator R-verapamil and TCDC, but not TUDC, lowered cell membrane order in a concentration-dependent manner and increased membrane fluidity of the resistant CH(R)C5 subline. TCDC and R-verapamil were without effect on the cell membrane fluidity of AUXB1 cells. These changes were accompanied by alterations in the fatty acid composition of the plasma membrane. Untreated sensitive AUXB1 cells had higher levels of unsaturated fatty acids than resistant CH(R)C5 cells. In CH(R)C5 cells, R-verapamil increased the content of poly-unsaturated fatty acids and TCDC, but not TUDC, increased the content of mono-unsaturated fatty acids. The results demonstrate that resistance modifiers such as verapamil may influence cytostatic drug action by producing structural changes to lipid domains in the plasma membrane.

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