Reversal Effect Of Delavirdine On MRP2-mediated Multidrug Resistance

Objective In the present study, the effect and the possible mechanism of delavirdine on MRP2-mediated multidrug resistance in LLC/cMOAT cells were examined. Methods MTT assay was used to determine the effects of delavirdine on proliferation of LLC/CMV and LLC/cMOAT cells. The inhibitory effects of vincristine (VCR), cisplatin (DDP), adriamycin (ADM) and etoposide (VP-16) used alone or in combination with delavirdine on the proliferation of LLC/CMV and LLC/cMOAT cells were evaluated by MTT assay. The cell cycle distribution, the apoptosis rate of the cells treated with different concentration of delavirdine and the intracellular concentration of ADM were determined by flow cytometry(FCM).Results①Delavirdine at the concentration of 4μmol.L-1and below showed no significant cytotoxicity to LLC/CMV and LLC/cMOAT cells.②The resistance of LLC/cMOAT cells to VCR,VP-16,ADM and DDP were 9.58,1.11,2.98 and 3.96 folds of that of LLC/CMV cells. When 2μmol.L-1 delavirdine was added, 5.21 and 2.55 folds respectively(P<0.05); when 4μmol/L delavirdine was added, the chemosensitivity of LLC/cMOAT cells to VCR and DDP were much higher(P<0.05) .while 2, 4μmol.L-1delavirdine made no significant changes to the chemosensitivity of LLC/CMV cells to VCR and DDP(P>0.05).③Cellular cycle analysis demonstrated that0,6,12,24 hours after co-cultured with delavirdine the amount of cells at G0/G1 phase increased from (38.92±0.15)% to (74.77±5.06)%. ④The cell apoptosis rate were 1.77%, 17.45% and 28.52% when treated with delavirdine at 2,4μmol.L-1 and VCR for 24h.⑤When treated with 2,4μmol.L-1 delavirdine, ADM accumulation in LLC/cMOAT cells were enhanced significantly(P<0.05).Conclusion DLV can partially reversed the multidrug resistance of LLC/cMOAT cells, and the reverse effect correlates to the concentration.The possible mechanism may involves the growth arrest at G1, increase of intracellular drug concentration and promoting apoptosis.