Telatinib reverses chemotherapeutic multidrug resistance by inhibiting ABCG2 efflux transporter in vitro and in vivo

Multidrug resistance (MDR) is phenomenon where cancer cells become resistant to anticancer drugs with different structures and mechanism of actions. 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 of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and cKIT, enhances the anticancer activity of the ABCG2 substrate anticancer drugs by inhibiting the ABCG2 efflux transporter activity. The incubation of ABCG2- overexpressing drug resistant cell lines with telatinib and ABCG2 substrate anticancer drugs significantly reduced cell viability, whereas telatinib alone did not significantly affect drug sensitive and drug resistant cell lines. Telatinib at 1 uM did not significantly alter the expression or localization of ABCG2 in ABCG2-overexpressing cell lines, based on experiments using Western blotting and immunofluorescence staining. Telatinib at 1 muM significantly enhanced the intracellular accumulation of [3H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1 muM significantly reduced the [3H]-MX efflux rate from ABCG2-overexpressing cells. 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 upon docking of telatinib to 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 nude mouse model. Immunohistochemical analysis of the excised tumor tissues from the animal study showed no significant change in the expression pattern of ABCG2. These results, provided that they can be translated to humans, suggest that telatinib, in combination with specific ABCG2 substrate drugs may be useful in treating tumors that overexpress ABCG2 transporter.