Cargando…

The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance

Tyrosine kinase inhibitors (TKIs) are important in managing lymphoid malignancies by targeting B-cell receptor signaling pathways. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase (Syk), currently in the phase II clinical trials for the treatment of chronic lymphocyt...

Descripción completa

Detalles Bibliográficos
Autores principales: Narayanan, Silpa, Wu, Zhuo-Xun, Wang, Jing-Quan, Ma, Hansu, Acharekar, Nikita, Koya, Jagadish, Yoganathan, Sabesan, Fang, Shuo, Chen, Zhe-Sheng, Pan, Yihang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315011/
https://www.ncbi.nlm.nih.gov/pubmed/34326700
http://dx.doi.org/10.7150/ijbs.61229
_version_ 1783729652047544320
author Narayanan, Silpa
Wu, Zhuo-Xun
Wang, Jing-Quan
Ma, Hansu
Acharekar, Nikita
Koya, Jagadish
Yoganathan, Sabesan
Fang, Shuo
Chen, Zhe-Sheng
Pan, Yihang
author_facet Narayanan, Silpa
Wu, Zhuo-Xun
Wang, Jing-Quan
Ma, Hansu
Acharekar, Nikita
Koya, Jagadish
Yoganathan, Sabesan
Fang, Shuo
Chen, Zhe-Sheng
Pan, Yihang
author_sort Narayanan, Silpa
collection PubMed
description Tyrosine kinase inhibitors (TKIs) are important in managing lymphoid malignancies by targeting B-cell receptor signaling pathways. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase (Syk), currently in the phase II clinical trials for the treatment of chronic lymphocytic leukemia. Syk is abundantly present in the cells of hematopoietic lineage that mediates cell proliferation, differentiation, and adhesion. In this current study, we evaluated the efficacy of GS-9973 to overcome multidrug resistance (MDR) due to the overexpression of the ABCG2 transporter in the non-small cell lung cancer (NSCLC) cell line, NCI-H460/MX20. In vitro, 3 μM of GS-9973 reversed the drug resistance of NCI-H460/MX20 cell line to mitoxantrone or doxorubicin. GS-9973, at 3 μM reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the protein level but did not alter the ABCG2 mRNA expression and subcellular localization of the ABCG2 protein compared to drug-resistant cells incubated with the vehicle. GS-9973 produced a moderate concentration-dependent increase in the ATPase activity of ABCG2 (EC(50) = 0.42 µM) and molecular docking data indicated that GS-9973 had a high affinity (-10.226 kcal/mol) for the substrate-binding site of ABCG2. Finally, HPLC analysis proved that the intracellular concentration of GS-9973 is not significantly different in both parental and resistant cell lines. In conclusion, our study suggests that in vitro, GS-9973 in combination with certain anticancer drugs, represent a strategy to overcome ABCG2-mediated MDR cancers.
format Online
Article
Text
id pubmed-8315011
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Ivyspring International Publisher
record_format MEDLINE/PubMed
spelling pubmed-83150112021-07-28 The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance Narayanan, Silpa Wu, Zhuo-Xun Wang, Jing-Quan Ma, Hansu Acharekar, Nikita Koya, Jagadish Yoganathan, Sabesan Fang, Shuo Chen, Zhe-Sheng Pan, Yihang Int J Biol Sci Research Paper Tyrosine kinase inhibitors (TKIs) are important in managing lymphoid malignancies by targeting B-cell receptor signaling pathways. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase (Syk), currently in the phase II clinical trials for the treatment of chronic lymphocytic leukemia. Syk is abundantly present in the cells of hematopoietic lineage that mediates cell proliferation, differentiation, and adhesion. In this current study, we evaluated the efficacy of GS-9973 to overcome multidrug resistance (MDR) due to the overexpression of the ABCG2 transporter in the non-small cell lung cancer (NSCLC) cell line, NCI-H460/MX20. In vitro, 3 μM of GS-9973 reversed the drug resistance of NCI-H460/MX20 cell line to mitoxantrone or doxorubicin. GS-9973, at 3 μM reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the protein level but did not alter the ABCG2 mRNA expression and subcellular localization of the ABCG2 protein compared to drug-resistant cells incubated with the vehicle. GS-9973 produced a moderate concentration-dependent increase in the ATPase activity of ABCG2 (EC(50) = 0.42 µM) and molecular docking data indicated that GS-9973 had a high affinity (-10.226 kcal/mol) for the substrate-binding site of ABCG2. Finally, HPLC analysis proved that the intracellular concentration of GS-9973 is not significantly different in both parental and resistant cell lines. In conclusion, our study suggests that in vitro, GS-9973 in combination with certain anticancer drugs, represent a strategy to overcome ABCG2-mediated MDR cancers. Ivyspring International Publisher 2021-06-22 /pmc/articles/PMC8315011/ /pubmed/34326700 http://dx.doi.org/10.7150/ijbs.61229 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Narayanan, Silpa
Wu, Zhuo-Xun
Wang, Jing-Quan
Ma, Hansu
Acharekar, Nikita
Koya, Jagadish
Yoganathan, Sabesan
Fang, Shuo
Chen, Zhe-Sheng
Pan, Yihang
The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance
title The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance
title_full The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance
title_fullStr The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance
title_full_unstemmed The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance
title_short The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance
title_sort spleen tyrosine kinase inhibitor, entospletinib (gs-9973) restores chemosensitivity in lung cancer cells by modulating abcg2-mediated multidrug resistance
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315011/
https://www.ncbi.nlm.nih.gov/pubmed/34326700
http://dx.doi.org/10.7150/ijbs.61229
work_keys_str_mv AT narayanansilpa thespleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT wuzhuoxun thespleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT wangjingquan thespleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT mahansu thespleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT acharekarnikita thespleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT koyajagadish thespleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT yoganathansabesan thespleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT fangshuo thespleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT chenzhesheng thespleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT panyihang thespleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT narayanansilpa spleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT wuzhuoxun spleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT wangjingquan spleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT mahansu spleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT acharekarnikita spleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT koyajagadish spleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT yoganathansabesan spleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT fangshuo spleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT chenzhesheng spleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance
AT panyihang spleentyrosinekinaseinhibitorentospletinibgs9973restoreschemosensitivityinlungcancercellsbymodulatingabcg2mediatedmultidrugresistance