Increase of vinblastine accumulation by inhibitors of calmodulin-dependent cell functions in rat ascites hepatoma AH66 cells.
ML-9, an inhibitor for myosin light chain kinase, and W-7, a calmodulin inhibitor, suppressed the efflux of vinblastine and increased the intracellular accumulation of vinblastine, but W-5, an inactive compound for calmodulin, did not so in rat ascites hepatoma AH66 cells, which have a multidrug-resistant phenotype. In sensitive counterpart AH66F cells, W-7 and ML-9 were less effective. W-7 and ML-9 did not interfere with [3H]azidopine photolabeling of P-glycoprotein in the plasma membrane from AH66 cells. While P-glycoprotein is reported to be superphosphorylated by protein kinases, W-7 did not influence the phosphorylation of the P-glycoprotein in AH66 cells. There may be an unknown Ca(2+)-calmodulin-dependent mechanism in the extrusion of vinblastine from AH66 cells.
Wakusawa
S
S
Research Laboratory for Development of Medicine, School of Pharmacy, Hokuriku University, Kanazawa, Japan.
Takeda
K
K
Miyamoto
K
K
Hidaka
H
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001386:Azides / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000502:physiology; D005260:Female; D007700:Kinetics; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011919:Rats, Inbred Strains; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001381:Azepines; D001386:Azides; D002147:Calmodulin; D004095:Dihydropyridines; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D013449:Sulfonamides; C056218:ML 9; D014747:Vinblastine; C041130:azidopine; C017967:W 7; C034700:N-(6-aminohexyl)-1-naphthalenesulfonamide; D009219:Myosin-Light-Chain Kinase