Reversal of vinblastine resistance by a new staurosporine derivative, NA-382, in P388/ADR cells.
Activities of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-staurosporine (NA-382), on cyclic AMP-dependent protein kinase (A-kinase), Ca2+/phospholipid dependent protein kinase (C-kinase), and drug resistance were investigated and compared with those of staurosporine. Protein kinase-inhibitory activity of NA-382 was lower but more selective to C-kinase than that of staurosporine. NA-382 was less toxic to P388 cells and at a non-cytotoxic concentration completely reversed the vinblastine (VBL) resistance of Adriamycin-resistant P388 (P388/ADR) cells without influence on the effect of VBL on the parental P388/S cells. However, the cytotoxicity of staurosporine was too high to give the combination effect with VBL. NA-382 dose-dependently increased VBL-accumulation and inhibited VBL-efflux in P388/ADR with higher potency than staurosporine. Both compounds inhibited the photolabeling of [3H]azidopine on 140-kDa P-glycoprotein in the plasma membrane from the resistant cells. These results suggest that a staurosporine analog, NA-382, reverses multidrug resistance by inhibiting the drug-efflux system or P-glycoprotein.
Research Laboratory for Development of Medicine, School of Pharmacy, Hokuriku University, Kanazawa, Japan.
K
K
Miyamoto
S
S
Wakusawa
K
K
Inoko
K
K
Takagi
M
M
Koyama
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001386:Azides / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism; D004095:Dihydropyridines / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics*; D007941:Leukemia P388 / Q000235:genetics; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000031:analogs & derivatives; D014747:Vinblastine / Q000378:metabolism* / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000470:Alkaloids; D001386:Azides; D004095:Dihydropyridines; D008562:Membrane Glycoproteins; C075317:N-ethoxycarbonyl-7-oxostaurosporine; D014747:Vinblastine; C041130:azidopine; D004317:Doxorubicin; D011493:Protein Kinase C; D019311:Staurosporine