Novel plant triterpenoid drug amooranin overcomes multidrug resistance in human leukemia and colon carcinoma cell lines

Amooranin (AMR), a plant terpenoid, isolated from Amoora rohituka, was investigated for its ability to overcome multidrug resistance in human leukemia and colon carcinoma cell lines. AMR IC50 values of multidrug-resistant leukemia (CEM/VLB) and cc;Con carcinoma (SW620/Ad-300) ce lines were higher (1.9- and 6-fold) than parental sensitive cell lines (CEM and SW620). AMR induced G(2)+M phase-arrest during cell cycle traverse in leukemia and colon carcinoma cell lines and the percentage of cells in G(2) + M phase increased in a dose-dependent manner. Coincubation of tumor cells with both DOX and AMR reversed DOX resistance in 104-fold DOX-resistant CEM/VLB and I I I-fold DOX-resistant SW620/Ad-300 cell lines with a dose modification factor of 50.9 and 99.6, respectively. Flow cytometric assay showed that AMR causes enhanced cellular DOX accumulation in a dose-dependent manner. AMR inhibits photolabeling of P. glycoprotein (P-gp) with [H-3]-azidopine and the blocking effect enhanced with increasing concentrations of AMR. Our results show that AMR competitively inhibits P-gp-mediated DOX efflux, suggestive of a mechanism underlying the enhanced DOX accumulation and reversal of multidrug resistance by AMR. (C) 2003 Wiley-Liss, Inc.