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

Abstract

Multidrug 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 μM did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines. Telatinib at 1 μM significantly enhanced the intracellular accumulation of [(3)H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1 μM significantly reduced the rate of [(3)H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibited ABCG2-mediated transport of [(3)H]-E₂17βG 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.

• Authors: Kamlesh Sodani, Atish Patel, Nagaraju Anreddy, Satyakam Singh, Dong-Hua Yang, Rishil J Kathawala, Priyank Kumar, Tanaji T Talele, Zhe-Sheng Chen
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 89 Issue 1 Pg. 52-61 (May 01 2014) ISSN: 1873-2968 [Electronic] England
• PMID: 24565910 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Neoplasm Proteins
• Pyridazines
• Pyridines
• telatinib

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (genetics, physiology)
• Animals
• Antineoplastic Agents (therapeutic use)
• Drug Resistance, Neoplasm
• Humans
• In Vitro Techniques
• Male
• Mice
• Mice, Nude
• Neoplasm Proteins (genetics, physiology)
• Pyridazines (therapeutic use)
• Pyridines (therapeutic use)