Influence of metabolic inhibitors on the intracellular accumulation and retention of adriamycin

We observed modulation of the intracellular accumulation and retention of a driamycin (ADR) by metabolic inhibitors in Ehrlich ascites tumor cells (wil d type EAT cells) and their ADR-resistant EAT strain. In the wild type EAT cells, ADR accumulation was increased by 0.2 mM of 2,4-dinitrophenol (2,4-D NP), 1 mM of sodium azide (NaN3) or 1 mM of potassium cyanide (KCN), which were the metabolic inhibitors and its efflux was inhibited by the metabolic inhibitors several fold. These results indicate that in wild type EAT cell s, one of the mechanisms which increase the intracellular accumulation of A DR involve inhibition of efflux which may be inhibited by these metabolic i nhibitors. In ADR-resistant EAT strain 2,4-DNP or KCN increased the ADR acc umulation, but NaN3 did nor affect it. Further; ADR efflux in the ADR-resis tant cells after incubation with the metabolic inhibitors were similar to t hat found in the control. These indicates that in the ADR-resistant cells, NaN3 does not affect ADR accumulation and retention, and that the increase in the ADR accumulation by KCN and 2,4-DNP was considered to be due to the influx rather than efflux. In addition, 2,4-DNP, NaN3 or KCN inhibited ADR efflux in the wild type GAT cells but not in the ADR-resistant EAT strain. These suggests that there is an efflux mechanism in the ADR-resistant EAT s train that involves an energy system that differs from the energy system in wild type EAT cells or does not depend on energy produced by the metabolic inhibitors.