Oncotarget

Research Papers:

Quizartinib (AC220) reverses ABCG2-mediated multidrug resistance: In vitro and in vivo studies

Jun Li, Priyank Kumar, Nagaraju Anreddy, Yun-Kai Zhang, Yi-Jun Wang, Yanglu Chen, Tanaji T. Talele, Kanav Gupta, Louis D. Trombetta and Zhe-Sheng Chen _

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Oncotarget. 2017; 8:93785-93799. https://doi.org/10.18632/oncotarget.21078

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Abstract

Jun Li1,2,*, Priyank Kumar1,*, Nagaraju Anreddy1, Yun-Kai Zhang1, Yi-Jun Wang1, Yanglu Chen1,3, Tanaji T. Talele1, Kanav Gupta1,4, Louis D. Trombetta1 and Zhe-Sheng Chen1

1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, New York, 11439, USA

2Department of Otolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China

3Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA

4Jericho High School, Jericho, NY, 11753, USA

*These authors have contributed equally to this work

Correspondence to:

Zhe-Sheng Chen, email: chenz@stjohns.edu

Louis D. Trombetta, email: trombetl@stjohns.edu

Keywords: quizartinib, ABCG2, ABCC1, MDR, reversal

Received: April 25, 2017     Accepted: June 26, 2017     Published: September 16, 2017

ABSTRACT

Previous reports have shown that some tyrosine kinase inhibitors (TKIs) could inhibit the ATP-binding cassette (ABC) transporters involved in multidrug resistance (MDR). Quizartinib (AC220), a potent class III receptor tyrosine kinase inhibitor (TKI), was synthesized to selectively inhibit FMS-like tyrosine kinase-3 (FLT3), a target in the treatment of acute myeloid leukemia (AML). Quizartinib is currently under clinical trials for FLT3 ITD and wild-type AML and is tested in combination with chemotherapy. While non-toxic to cell lines, quizartinib at 3 μM showed significant reversal effect on wild-type and mutant ABCG2 (R482T)-mediated MDR, and only a moderate reversal effect on mutant ABCG2 (R482G)-mediated MDR. Results also showed that quizartinib reversed MDR not by reducing the expression of ABCG2 protein, but by antagonizing the drug efflux function and increasing the intracellular accumulation of substrate anticancer drugs in ABCG2-overexpressing cells. Importantly, quizartinib at 30 mg/kg strongly enhanced the effect of topotecan (3 mg/kg) in ABCG2-overexpressing (H460/MX20) xenografts in athymic nude mice. These results demonstrated that quizartinib potentiates the antineoplastic activity of wild-type and R482T mutant ABCG2 substrates. These findings may be useful in clinical practice for cancer combination therapy with quizartinib.


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