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.
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.
Authors: Guan-Nan Zhang; Yun-Kai Zhang; Yi-Jun Wang; Anna Maria Barbuti; Xi-Jun Zhu; Xin-Yue Yu; Ai-Wen Wen; John N D Wurpel; Zhe-Sheng Chen Journal: Pharmacol Res Date: 2017-01-25 Impact factor: 7.658
Authors: Hui Zhang; Rishil J Kathawala; Yi-Jun Wang; Yun-Kai Zhang; Atish Patel; Suneet Shukla; Robert W Robey; Tanaji T Talele; Charles R Ashby; Suresh V Ambudkar; Susan E Bates; Li-Wu Fu; Zhe-Sheng Chen Journal: Int J Biochem Cell Biol Date: 2014-04-12 Impact factor: 5.085