Lysosomal Exocytosis and Drug Resistance in K562 Cells

Lysosomal exocytosis induced by the sequestration of hydrophobic weak-base drugs has been proposed as a mechanism of drug resistance (DR), although direct evidence for its quantitative relevance is lacking. Here, we compared the kinetics of lysosomal exocytosis with those of ABCB1-mediated active drug efflux and passive drug efflux by diffusion in K562 cells. Drug panels were selected according to the process investigated, with passive efflux assessed using compounds representing both the lysosomal exocytosis and ABCB1 substrate groups. Lysosomal exocytosis was quantified using FITC-dextran-labelled lysosomes and flow cytometry. K562 cells with high or moderate ABCB1 expression were used to determine active efflux, whereas parental K562 cells lacking detectable ABCB1 expression were used to determine passive efflux. Drug-induced lysosomal exocytosis was slow, with the intracellular FITC-dextran content decreasing to approximately 50% of its initial value after 5–8 h at 30 μM and 8–12 h at 10 μM. In contrast, ABCB1-mediated and passive efflux exhibited half-times of approximately 12–20 and 23–36 min, respectively. Moreover, measurable lysosomal exocytosis occurred only at high micromolar drug concentrations associated with off-target cytotoxicity. Thus, lysosomal exocytosis is unlikely to represent a quantitatively relevant mechanism of drug resistance in K562 cells.