The Novel BCR-ABL and FLT3 Inhibitor Ponatinib Is a Potent Inhibitor of the MDR-Associated ATP-Binding Cassette Transporter ABCG2

Abstract

Ponatinib is a novel tyrosine kinase inhibitor with potent activity against BCR-ABL with mutations including T315I, and also against fms-like tyrosine kinase 3 (FLT3). We tested interactions between ponatinib at pharmacologically relevant concentrations of 50 to 200 nM and the multidrug resistance-associated ATP-binding cassette (ABC) proteins ABCB1, ABCC1 and ABCG2. Ponatinib enhanced uptake of substrates of ABCG2 and ABCB1, but not ABCC1, in cells overexpressing these proteins, with a greater effect on ABCG2 than on ABCB1. Ponatinib potently inhibited [125I]-IAAP binding to ABCG2 and ABCB1, indicating binding to their drug substrate sites, with IC50s of 0.04 μM and 0.63 μM, respectively. Ponatinib stimulated ABCG2 ATPase activity in a concentration-dependent manner and stimulated ABCB1 ATPase activity at low concentrations, consistent with it being a substrate of both proteins at pharmacologically relevant concentrations. The ponatinib IC50s of BCR-ABL-expressing K562 cells transfected with ABCB1 and ABCG2 were approximately the same as and 2-fold higher than that of K562, respectively, consistent with ponatinib being a substrate of both proteins, but inhibiting its own transport, and resistance was also attenuated to a small degree by ponatinib-induced downregulation of ABCB1 and ABCG2 cell surface expression on resistant K562 cells. Ponatinib at pharmacologically relevant concentrations produced synergistic cytotoxicity with ABCB1 and ABCG2 substrate chemotherapy drugs and enhanced apoptosis induced by these drugs, including daunorubicin, mitoxantrone, topotecan and flavopiridol, in cells overexpressing these transport proteins. Combinations of ponatinib and chemotherapy drugs warrant further testing.

Delivery of miR-375 and doxorubicin hydrochloride by lipid-coated hollow mesoporous silica nanoparticles to overcome multiple drug resistance in hepatocellular carcinoma

“…Then, the dialysis bag was dispersed in 30 mL 10 mM PBS at pH 7.4 and pH 5.0, respectively, and kept stirring under the dark. The concentration of DOX in PBS was detected with a UV spectrophotometer at 1,3,5,6,8,12,20,24,30,48, and 72 h. At each time point, 1.0 mL of the external buffer was collected and replaced by 1.0 mL of fresh buffer.…”

“…A known mechanism of MDR in cancer cells is the overexpression of ATP-binding cassette (ABC) transporter proteins, which pump out chemical agents and thus generate an MDR phenotype. [2][3][4] A well-studied…”

“…When tumors grew to 500 mm 3 , LHD or free DOX was injected via the lateral tail vein at 8 mg/kg DOX. At different time points after the injection (0.5, 1, 2, 4, 8, 12, and 24 h), 500 μL blood was collected in heparin-treated tubes and then centrifuged (5,000 rpm, 5 min) at room temperature to obtain plasma.…”

“…antitumor effects of lhD/mir-375 in xenograft and primary tumor model For antitumor efficacy study in the xenograft tumor model, mice were randomly divided into five groups (n=6) when tumor volume reached ~100 mm 3 . Saline, DOX, LH/miR-375, LHD, or LHD/miR-375 were injected via tail vein at 6 mg/kg DOX and/or 4 nmol/kg miR-375 three times on days 10, 16, and 22 after HepG2/ADR cell inoculation.…”

Selective Inhibition of Human Equilibrative and Concentrative Nucleoside Transporters by BCR-ABL Kinase Inhibitors

“…The cellular uptake of dasatinib was mainly passive and not dependent on organic cation transporters (9). Ponatinib was a potent inhibitor of ABCG2 (17), whereas bosutinib was not a substrate of ABCB1 or ABCG2 (8).…”