REVERSAL OF MULTIDRUG-RESISTANCE PHENOTYPE BY SURFACTANTS - RELATIONSHIP TO MEMBRANE LIPID FLUIDITY

Previous studies have suggested that multidrug resistance (MDR) revers al by polyoxyethylene surfactants involves alterations in plasma membr ane lipid physical state of resistant cells as one of the possible mec hanism(s). To date, however, a detailed and critical examination of th e relationship between membrane lipid fluidity and MDR reversal by the se surfactants has not been performed. In the present studies, therefo re, a series of experiments were conducted to critically examine the r ole of membrane lipid physical state in MDR reversal by employing a un ique class of clinically important nontoxic lipophilic surfactants and the KB-8-5-11 drug-resistant cell line. MDR reversal was assessed by rhodamine-123 uptake. The effect of surfactants on plasma membrane lip id fluidity of these cells was assessed utilizing a fluorescence polar ization technique with fluorophores DPH, TMA, DPH, 2-AS, and 12-AS. Ou r studies demonstrated that: (i) in vitro addition of active MDR-rever sing surfactants (Solutol HS-15, Tween 40, and Cremophor EL, 10 mu g/m l each) decreased lipid fluidity of isolated crude plasma membranes of resistant cells; (ii) the inactive surfactants (octylglucoside, hecam eg) failed to influence membrane lipid fluidity; (iii) cells grown in the presence of active surfactants also exhibited a decreased plasma m embrane lipid fluidity as measured with intact cells utilizing the pro be TMA.DPH; and (iv) active surfactants did not influence lifetimes of the excited state of the fluorophores, These findings demonstrate tha t decrease of the plasma membrane lipid fluidity of KB 8-5-11 resistan t cells may be one of the important mechanism(s) of MDR reversal by po lyoxyethylene surfactants. (C) 1995 Academic Press, Inc.