Reversal of multidrug resistance phenotype by surfactants: relationship to membrane lipid fluidity.
Previous studies have suggested that multidrug resistance (MDR) reversal by polyoxyethylene surfactants involves alterations in plasma membrane lipid physical state of resistant cells as one of the possible mechanism(s). To date, however, a detailed and critical examination of the relationship between membrane lipid fluidity and MDR reversal by these surfactants has not been performed. In the present studies, therefore, a series of experiments were conducted to critically examine the role of membrane lipid physical state in MDR reversal by employing a unique 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 lipid fluidity of these cells was assessed utilizing a fluorescence polarization technique with fluorophores DPH, TMA. DPH, 2-AS, and 12-AS. Our studies demonstrated that: (i) in vitro addition of active MDR-reversing surfactants (Solutol HS-15, Tween 40, and Cremophor EL, 10 micrograms/ml each) decreased lipid fluidity of isolated crude plasma membranes of resistant cells; (ii) the inactive surfactants (octylglucoside, hecameg) failed to influence membrane lipid fluidity; (iii) cells grown in the presence of active surfactants also exhibited a decreased plasma membrane lipid fluidity as measured with intact cells utilizing the probe TMA.DPH; and (iv) active surfactants did not influence lifetimes of the excited state of the fluorophores. These findings demonstrate that decrease of the plasma membrane lipid fluidity of KB 8-5-11 resistant cells may be one of the important mechanism(s) of MDR reversal by polyoxyethylene surfactants.
Dudeja
P K
PK
Department of Medicine, University of Illinois at Chicago, USA.
Anderson
K M
KM
Harris
J S
JS
Buckingham
L
L
Coon
J S
JS
D002460:Cell Line; D004161:Diphenylhexatriene / Q000031:analogs & derivatives; D018432:Drug Resistance, Multiple / Q000235:genetics* / Q000502:physiology; D005434:Flow Cytometry; D005454:Fluorescence Polarization; D005456:Fluorescent Dyes; D005960:Glucosides / Q000494:pharmacology; D006801:Humans; D008560:Membrane Fluidity / Q000187:drug effects* / Q000502:physiology; D008563:Membrane Lipids / Q000378:metabolism*; D010641:Phenotype; D011092:Polyethylene Glycols; D020112:Rhodamine 123; D012235:Rhodamines; D013229:Stearic Acids; D013501:Surface-Active Agents / Q000494:pharmacology*
D005456:Fluorescent Dyes; D005960:Glucosides; D008563:Membrane Lipids; D012235:Rhodamines; D013229:Stearic Acids; D013501:Surface-Active Agents; D004161:Diphenylhexatriene; D020112:Rhodamine 123; C018619:octyl-beta-D-glucoside; D011092:Polyethylene Glycols; C067028:Solutol HS 15; C033628:1-(4-(trimethylamino)phenyl)-6-phenylhexa-1,3,5-triene