AIM: This study aimed to investigate the mechanism of reversal of multidrug 
resistance mediated by ABC transporters with tivozanib (AV-951 and KRN-951). 
Tivozanib is a potent inhibitor of VEGF-1, -2 and -3 receptors.
MATERIALS & METHODS: ABCB1- and ABCG2-overexpressing cell lines were treated 
with respective substrate antineoplastic agents in the presence or absence of 
tivozanib.
RESULTS: The results indicate that tivozanib can significantly reverse 
ABCB1-mediated resistance to paclitaxel, vinblastine and colchicine, as well as 
ABCG2-mediated resistance to mitoxantrone, SN-38 and doxorubicin. Drug efflux 
assays showed that tivozanib increased the intracellular accumulation of 
substrates by inhibiting the ABCB1 and ABCG2 efflux activity. Furthermore, at a 
higher concentration, tivozanib inhibited the ATPase activity of both ABCB1 and 
ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2.
CONCLUSION: We conclude that tivozanib at noncytotoxic concentrations has the 
previously unknown activity of reversing multidrug resistance mediated by ABCB1 
and ABCG2 transporters.