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Sodani K , Patel A , Anreddy N , Singh S , Yang DH , Kathawala RJ , Kumar P , Talele TT , Chen ZS
Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo
Biochem Pharmacol. 2014 May 1;89(1) :52-61
AbstractMultidrug resistance (MDR) is a phenomenon where cancer cells become simultaneously resistant to anticancer drugs with different structures and mechanisms of action. MDR has been shown to be associated with overexpression of ATP-binding cassette (ABC) transporters. Here, we report that telatinib, a small molecule tyrosine kinase inhibitor, enhances the anticancer activity of ABCG2 substrate anticancer drugs by inhibiting ABCG2 efflux transporter activity. Co-incubation of ABCG2-overexpressing drug resistant cell lines with telatinib and ABCG2 substrate anticancer drugs significantly reduced cellular viability, whereas telatinib alone did not significantly affect drug sensitive and drug resistant cell lines. Telatinib at 1 muM did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines. Telatinib at 1 muM significantly enhanced the intracellular accumulation of [(3)H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1 muM significantly reduced the rate of [(3)H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibited ABCG2-mediated transport of [(3)H]-E(2)17betaG in ABCG2 overexpressing membrane vesicles. Telatinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that telatinib might be a substrate of ABCG2. Binding interactions of telatinib were found to be in transmembrane region of homology modeled human ABCG2. In addition, telatinib (15 mg/kg) with doxorubicin (1.8 mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. These results, provided that they can be translated to humans, suggesting that telatinib, in combination with specific ABCG2 substrate drugs may be useful in treating tumors that overexpress ABCG2.
Notes1873-2968 Sodani, Kamlesh Patel, Atish Anreddy, Nagaraju Singh, Satyakam Yang, Dong-Hua Kathawala, Rishil J Kumar, Priyank Talele, Tanaji T Chen, Zhe-Sheng R15 CA143701/CA/NCI NIH HHS/United States In Vitro Journal Article England Biochem Pharmacol. 2014 May 1;89(1):52-61. doi: 10.1016/j.bcp.2014.02.012. Epub 2014 Feb 22.