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.