A newly synthesized 1,4-benzothiazipine derivate, 4-[3-(4-benzylpiperidin-1-yl) 
propionyl]-7-methoxy-2,3,4,5-tetrahydro-1, 4-benzothiazepine monohydrochloride 
(JTV-519) was examined for its ability to reverse P-glycoprotein (P-gp) and 
multidrug resistance protein 1 (MRP1) mediated multidrug resistance (MDR) in 
K562/MDR and KB/MRP cells, respectively. JTV-519 at 3 microM reversed the 
resistance of K562/MDR cells to vincristine (VCR), taxol, etoposide (VP16), 
adriamycin (ADM) and actinomycin D and at 0.5 or 1 microM reversed their 
resistance to STI571. JTV-519 at 10 microM enhanced the accumulation of ADM in 
K562/MDR cells to the level in parental K562 cells and inhibited the efflux of 
ADM from K562/MDR cells. Photoaffinity labeling of P-gp with 3H-azidopine was 
almost completely inhibited by 500 microM JTV-519. JTV-519 at 3 microM also 
partially reversed the resistance of KB/MRP cells to VCR and at 500 microM 
partially inhibited the photoaffinity labeling of MRP1 with 
(125)I-II-azidophenyl agosterol A (125I-azidoAG-A). These results suggest that 
JTV-519 reversed the resistance to the anti-cancer agents in P-gp and MRP1 
overexpressing multidrug-resistant cells by directly binding to P-gp and MRP1, 
and competitively inhibiting transport of the anti-cancer agents.