Reversal of multidrug resistance and increase in plasma membrane fluidity in CHO cells with R-verapamil and bile salts.
Studies with multidrug resistance modifiers indicate that perturbations of the cell membrane structure may influence P-glycoprotein (P-gp)-mediated drug transport. We describe studies of plasma membrane order using electron-paramagnetic resonance (EPR) in resistant (CH(R)C5) and sensitive (AUXB1) chinese hamster ovary cells treated with R-verapamil and bile salts. Cell growth rates were determined in presence of doxorubicin mitomycin and cisplatin. The plasma membrane order in untreated resistant cells was higher than in the sensitive cells. Both the bile salt taurochenodeoxycholate (TCDC; 0.2-1.6 mM) and R-verapamil (1-3 microM) lowered the membrane order in the CH(R)C5 cells to that in the sensitive cells and reversed the resistance to doxorubicin and mitomycin. The bile salt tauroursodeoxycholate (TUDC; 0.2-3 mM) did not lower membrane order and did not sensitise CH(R)C5 cells. Neither R-verapamil, TCDC nor TUDC reduced the membrane order of the sensitive cells AUXB1 cells. These results support the view that changes in multidrug resistance in Chinese hamster ovary cells and P-gp function are associated with alterations in the fluidity of the plasma membrane.
Schuldes
H
H
Cellular Research Laboratory, Urological Clinic, Center of Surgery, J.-W. Goethe-University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt, Main, Germany.
Dolderer
J H
JH
Zimmer
G
G
Knobloch
J
J
Bickeböller
R
R
Jonas
D
D
Woodcock
B G
BG
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D006224:Cricetinae; D003412:Cricetulus; D004317:Doxorubicin / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D008560:Membrane Fluidity / Q000187:drug effects*; D016685:Mitomycin / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*
D000970:Antineoplastic Agents; D016685:Mitomycin; D013655:Taurochenodeoxycholic Acid; D004317:Doxorubicin; D014700:Verapamil; D002945:Cisplatin