Reversal effect of vatalanib on BCRP-mediated multidrug resistance / 中国药理学通报

ABSTRACT

Aim To investigate the reversal effect of vatalanib, a novel kinase inhibitor, on multidrug re-sistance in cancer cells and its mechanism. Methods The cytotoxicity and reversal effects of vatalanib were evaluated in both resistant and sensitive tumor cell lines by MTS or SRB assays. The intracellular accumu-lation of fluorescence substrates ( Rh-123 , MX and ADR for P-gp, BCRP, MRP1, respectively) were ana-lysed by flow cytometry. Western blot or qRT-PCR was used to determine the protein or mRNA expression lev-el of BCRP. The effect of vatalanib on ATPase activity of BCRP was determined using crude membranes pre-pared from HEK293/ABCG2 cells. Results Vata-lanib at the nontoxic dose ( 5 μmol · L-1 ) potentially reversed BCRP-mediated MDR in cancer cells, howev-er it had no effect on P-gp or MRP1 mediated MDR. Vatalanib did not alter the intracellular accumulation of MX in HEK 2 9 3 / ABCG 2 , and had no influence on the BCRP-mediated drug efflux. The ATPase assay indica-ted that vatalanib may serve as a substrate of BCRP. Furthermore, vatalanib dramatically suppressed levels of both the protein and mRNA expression of BCRP in concentration-and time-dependent manners. However, reversal concentration of vatalanib had no influence on the total and phosphorylated forms of AKT and ERK1/ 2 in resistant cancer cells. Conclusion Vatalanib could significantly reverse BCRP-mediated MDR with specificity, and its mechanism may correlate with the down-regulation levels of BCRP both mRNA and pro-tein in resistant cancer cells.