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Blockade of the forward Na(+)/Ca(2+) exchanger suppresses the growth of glioblastoma cells through Ca(2+)‐mediated cell death

BACKGROUND AND PURPOSE: The Na(+)/Ca(2+) exchanger (NCX) working in either forward or reverse mode participates in maintaining intracellular Ca(2+) ([Ca(2+)](i)) homeostasis, which is essential for determining cell fate. Previously, numerous blockers targeting reverse or forward NCX have been develo...

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Autores principales: Hu, Hui‐Jie, Wang, Shan‐Shan, Wang, Yan‐Xia, Liu, Yan, Feng, Xue‐Mei, Shen, Ying, Zhu, Liang, Chen, Hong‐Zhuan, Song, Mingke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609550/
https://www.ncbi.nlm.nih.gov/pubmed/31034096
http://dx.doi.org/10.1111/bph.14692
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author Hu, Hui‐Jie
Wang, Shan‐Shan
Wang, Yan‐Xia
Liu, Yan
Feng, Xue‐Mei
Shen, Ying
Zhu, Liang
Chen, Hong‐Zhuan
Song, Mingke
author_facet Hu, Hui‐Jie
Wang, Shan‐Shan
Wang, Yan‐Xia
Liu, Yan
Feng, Xue‐Mei
Shen, Ying
Zhu, Liang
Chen, Hong‐Zhuan
Song, Mingke
author_sort Hu, Hui‐Jie
collection PubMed
description BACKGROUND AND PURPOSE: The Na(+)/Ca(2+) exchanger (NCX) working in either forward or reverse mode participates in maintaining intracellular Ca(2+) ([Ca(2+)](i)) homeostasis, which is essential for determining cell fate. Previously, numerous blockers targeting reverse or forward NCX have been developed and studied in ischaemic tissue injury but barely examined in glioblastoma for the purpose of anti‐tumour therapy. We assessed the effect of NCX blockers on glioblastoma growth and whether NCX can become a therapeutic target. EXPERIMENTAL APPROACH: Patch‐clamp recording, Ca(2+) imaging, flow cytometry, and Western blot were used to study the effects of specific and non‐specific NCX blockers on cultured glioblastoma cells. In vivo bioluminescent imaging was used to measure effects on grafted glioblastoma. KEY RESULTS: Selectively blocking the reverse NCX with SEA0400, SN‐6, and YM‐244769 did not affect tumour cell viability. Blocking the forward NCX with bepridil, CB‐DMB, or KB‐R7943 elevated [Ca(2+)](i) and killed glioblastoma cells. Bepridil and CB‐DMB caused Ca(2+)‐dependent cell cycle arrest together with apoptosis, which were all attenuated by a Ca(2+) chelator BAPTA‐AM. Systemic administration of bepridil inhibited growth of brain‐grafted glioblastoma. Bepridil did not appear to have a cytotoxic effect on human astrocytes, which have higher functional expression of NCX than glioblastoma cells. CONCLUSIONS AND IMPLICATIONS: Low expression of the NCX makes glioblastoma cells sensitive to disturbance of [Ca(2+)](i). Interventions designed to block the forward NCX can cause Ca(2+)‐mediated injury to glioblastoma thus having therapeutic potential. Bepridil could be a lead compound for developing new anti‐tumour drugs.
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spelling pubmed-66095502019-12-05 Blockade of the forward Na(+)/Ca(2+) exchanger suppresses the growth of glioblastoma cells through Ca(2+)‐mediated cell death Hu, Hui‐Jie Wang, Shan‐Shan Wang, Yan‐Xia Liu, Yan Feng, Xue‐Mei Shen, Ying Zhu, Liang Chen, Hong‐Zhuan Song, Mingke Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: The Na(+)/Ca(2+) exchanger (NCX) working in either forward or reverse mode participates in maintaining intracellular Ca(2+) ([Ca(2+)](i)) homeostasis, which is essential for determining cell fate. Previously, numerous blockers targeting reverse or forward NCX have been developed and studied in ischaemic tissue injury but barely examined in glioblastoma for the purpose of anti‐tumour therapy. We assessed the effect of NCX blockers on glioblastoma growth and whether NCX can become a therapeutic target. EXPERIMENTAL APPROACH: Patch‐clamp recording, Ca(2+) imaging, flow cytometry, and Western blot were used to study the effects of specific and non‐specific NCX blockers on cultured glioblastoma cells. In vivo bioluminescent imaging was used to measure effects on grafted glioblastoma. KEY RESULTS: Selectively blocking the reverse NCX with SEA0400, SN‐6, and YM‐244769 did not affect tumour cell viability. Blocking the forward NCX with bepridil, CB‐DMB, or KB‐R7943 elevated [Ca(2+)](i) and killed glioblastoma cells. Bepridil and CB‐DMB caused Ca(2+)‐dependent cell cycle arrest together with apoptosis, which were all attenuated by a Ca(2+) chelator BAPTA‐AM. Systemic administration of bepridil inhibited growth of brain‐grafted glioblastoma. Bepridil did not appear to have a cytotoxic effect on human astrocytes, which have higher functional expression of NCX than glioblastoma cells. CONCLUSIONS AND IMPLICATIONS: Low expression of the NCX makes glioblastoma cells sensitive to disturbance of [Ca(2+)](i). Interventions designed to block the forward NCX can cause Ca(2+)‐mediated injury to glioblastoma thus having therapeutic potential. Bepridil could be a lead compound for developing new anti‐tumour drugs. John Wiley and Sons Inc. 2019-06-17 2019-08 /pmc/articles/PMC6609550/ /pubmed/31034096 http://dx.doi.org/10.1111/bph.14692 Text en © 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Papers
Hu, Hui‐Jie
Wang, Shan‐Shan
Wang, Yan‐Xia
Liu, Yan
Feng, Xue‐Mei
Shen, Ying
Zhu, Liang
Chen, Hong‐Zhuan
Song, Mingke
Blockade of the forward Na(+)/Ca(2+) exchanger suppresses the growth of glioblastoma cells through Ca(2+)‐mediated cell death
title Blockade of the forward Na(+)/Ca(2+) exchanger suppresses the growth of glioblastoma cells through Ca(2+)‐mediated cell death
title_full Blockade of the forward Na(+)/Ca(2+) exchanger suppresses the growth of glioblastoma cells through Ca(2+)‐mediated cell death
title_fullStr Blockade of the forward Na(+)/Ca(2+) exchanger suppresses the growth of glioblastoma cells through Ca(2+)‐mediated cell death
title_full_unstemmed Blockade of the forward Na(+)/Ca(2+) exchanger suppresses the growth of glioblastoma cells through Ca(2+)‐mediated cell death
title_short Blockade of the forward Na(+)/Ca(2+) exchanger suppresses the growth of glioblastoma cells through Ca(2+)‐mediated cell death
title_sort blockade of the forward na(+)/ca(2+) exchanger suppresses the growth of glioblastoma cells through ca(2+)‐mediated cell death
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609550/
https://www.ncbi.nlm.nih.gov/pubmed/31034096
http://dx.doi.org/10.1111/bph.14692
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