Novel mechanism of N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine in potentiation of antitumor drug action on multidrug-resistant and sensitive Chinese hamster cells.
The mechanism of the synthetic isoprenoid N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine (SDB-ethylenediamine) in potentiating antitumor drug action against multidrug-resistant cells was comparatively studied with other potentiators such as verapamil and cepharanthine. SDB-ethylenediamine increased the accumulation of [3H]daunorubicin (DNR) in Chinese hamster V79 (V79/S) and its multidrug-resistant mutant (V79/ADM) cells. Even after SDB-ethylenediamine was removed from the medium, its effect continued. But when verapamil was removed from the medium, its effect disappeared immediately. Unlike verapamil and cepharanthine, SDB-ethylenediamine did not greatly inhibit the efflux of [3H]DNR from V79/ADM, the binding of [3H]vinblastine to membrane vesicles of V79/ADM, or the binding of [3H]azidopine to P-glycoprotein in the cytoplasmic membrane of V79/ADM. It did stimulate the influx of [3H]DNR into the ATP-depleted cells of V79/S and V79/ADM. Thus, SDB-ethylenediamine uniquely potentiates antitumor drugs. The increased intracellular accumulation of antitumor drugs in the presence of SDB-ethylenediamine is due not only to the inhibition of active efflux but also to the stimulation of the influx of antitumor drugs.
Tomida
A
A
Institute of Applied Microbiology, University of Tokyo.
Tatsuta
T
T
Suzuki
H
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001386:Azides / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003630:Daunorubicin / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D004357:Drug Synergism; D005029:Ethylenediamines / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001386:Azides; D004095:Dihydropyridines; D005029:Ethylenediamines; D008562:Membrane Glycoproteins; D013729:Terpenes; C048678:N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine; D014747:Vinblastine; C041130:azidopine; D004317:Doxorubicin; D014700:Verapamil; D003630:Daunorubicin