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

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 maj...

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Autores principales: Kathawala, Rishil J., Wei, Liuya, Anreddy, Nagaraju, Chen, Kang, Patel, Atish, Alqahtani, Saeed, Zhang, Yun-Kai, Wang, Yi-Jun, Sodani, Kamlesh, Kaddoumi, Amal, Ashby, Charles R., Chen, Zhe-Sheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381611/
https://www.ncbi.nlm.nih.gov/pubmed/25402202
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author Kathawala, Rishil J.
Wei, Liuya
Anreddy, Nagaraju
Chen, Kang
Patel, Atish
Alqahtani, Saeed
Zhang, Yun-Kai
Wang, Yi-Jun
Sodani, Kamlesh
Kaddoumi, Amal
Ashby, Charles R.
Chen, Zhe-Sheng
author_facet Kathawala, Rishil J.
Wei, Liuya
Anreddy, Nagaraju
Chen, Kang
Patel, Atish
Alqahtani, Saeed
Zhang, Yun-Kai
Wang, Yi-Jun
Sodani, Kamlesh
Kaddoumi, Amal
Ashby, Charles R.
Chen, Zhe-Sheng
author_sort Kathawala, Rishil J.
collection PubMed
description 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 μM), 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 × 6), in combination with paclitaxel (15 mg/kg, i.p., q3d × 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.
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spelling pubmed-43816112015-04-09 The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study Kathawala, Rishil J. Wei, Liuya Anreddy, Nagaraju Chen, Kang Patel, Atish Alqahtani, Saeed Zhang, Yun-Kai Wang, Yi-Jun Sodani, Kamlesh Kaddoumi, Amal Ashby, Charles R. Chen, Zhe-Sheng Oncotarget Research Paper 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 μM), 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 × 6), in combination with paclitaxel (15 mg/kg, i.p., q3d × 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. Impact Journals LLC 2014-10-28 /pmc/articles/PMC4381611/ /pubmed/25402202 Text en Copyright: © 2015 Kathawala et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Kathawala, Rishil J.
Wei, Liuya
Anreddy, Nagaraju
Chen, Kang
Patel, Atish
Alqahtani, Saeed
Zhang, Yun-Kai
Wang, Yi-Jun
Sodani, Kamlesh
Kaddoumi, Amal
Ashby, Charles R.
Chen, Zhe-Sheng
The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study
title The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study
title_full The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study
title_fullStr The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study
title_full_unstemmed The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study
title_short The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study
title_sort small molecule tyrosine kinase inhibitor nvp-bhg712 antagonizes abcc10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381611/
https://www.ncbi.nlm.nih.gov/pubmed/25402202
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