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The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study.

ABSTRACT: Paclitaxel exhibits clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multi-drug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. Here, we determine the effect of NVP-BHG712, a specific EphB4 receptor inhibitor, on 1) paclitaxel resistance in HEK293 cells transfected with ABCC10, 2) the growth of tumors in athymic nude mice that received NVP-BHG712 and paclitaxel systemically and 3) the pharmacokinetics of paclitaxel in presence or absence of NVP-BHG712. NVP-BHG712 (0.5 ?M), in HEK293/ABCC10 cells, significantly enhanced the intracellular accumulation of paclitaxel by inhibiting the efflux activity of ABCC10 without altering the expression level of the ABCC10 protein. Furthermore, NVP-BHG712 (25 mg/kg, p.o., q3d x 6), in combination with paclitaxel (15 mg/kg, i.p., q3d x 6), significantly inhibited the growth of ABCC10-expressing tumors in athymic nude mice. NVP-BHG712 administration significantly increased the levels of paclitaxel in the tumors but not in plasma compared to paclitaxel alone. The combination of NVP-BHG712 and paclitaxel could serve as a novel and useful therapeutic strategy to attenuate paclitaxel resistance mediated by the expression of the ABCC10 transporter.

SUBMITTER: Kathawala RJ

PROVIDER: S-EPMC4381611 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study.

Kathawala Rishil J RJ Wei Liuya L Anreddy Nagaraju N Chen Kang K Patel Atish A Alqahtani Saeed S Zhang Yun-Kai YK Wang Yi-Jun YJ Sodani Kamlesh K Kaddoumi Amal A Ashby Charles R CR Chen Zhe-Sheng ZS

Oncotarget 20150101 1

Paclitaxel exhibits clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multi-drug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. Here, we determine the effect of NVP-BHG712, a specific EphB4 receptor inhibitor, on 1) paclitaxel resistance in HEK293 cells transfected with ABCC10, 2) the grow ...[more]

PMID: 25402202

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Dataset Information

The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study.

Publications

The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study.

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