The effect of fatty acids and analogues upon intracellular levels of doxorubicin in cells displaying P-glycoprotein mediated multidrug resistance

Multidrug resistance mediated by overexpression of P-glycoprotein (P-gp) is a major obstacle in the chemotherapeutic management of cancer. The objecti ves of the current work were to examine if fatty acids affect the intracell ular transport and dynamics of doxorubicin in drug-resistant cancer cell li nes, and to assess if such effects were mediated through modulation of P-gp efflux pump activity. Among the range of fatty acids tested in this study, eicosapentaenoic acid diester (EPADI) increased doxorubicin accumulation [ A] to 137% and retention [R] to 212% in doxorubicin-resistant MCF-7/ADR bre ast carcinoma cells, and [A] to 147% and [R] to 163% in vinblastine-resista nt KBV1 nasopharyngeal carcinoma cells. Consistent with EPADI-induced incre ases in intracellular doxorubicin concentrations, EPADI (10 mug/ml) sensiti zed MCF-7/ADR cells to the cytotoxic effects of doxorubicin (1 mug/ml) as a ssessed by MTT assay (viability < 50% of control), while EPADI itself displ ayed no cytotoxicity, The combination of EPADI (10 <mu>g/ml) with verapamil (1 muM) resulted in a considerable increase in the [A] and [R] of the mode l P-gp substrate rhodamine-123 within drug-resistant cells compared to when either agent were used alone. KBV1 cells treated with combination of EPADI (10 mug/ml) and verapamil (1 muM) achieved 160% and 1120% greater [A] and [R] of rhodamine-123, respectively, compared to untreated cells. The P-gp m odulatory effects of EPADI either alone, or as part of a combination with m ore potent inhibitors, should be further investigated.