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Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells

Martin Schepelmann, Nadja Kupper, Marta Sladczyk, Bethan Mansfield, Teresa Manhardt, Karina Piatek, Luca Iamartino, Daniela Riccardi, Benson M. Kariuki, Marcella Bassetto, Enikö Kallay

International Journal of Molecular Sciences, Volume: 22, Issue: 18, Start page: 10124

Swansea University Author: Marcella Bassetto

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DOI (Published version): 10.3390/ijms221810124

Abstract

Pharmacological allosteric agonists (calcimimetics) of the extracellular calcium-sensing receptor (CaSR) have substantial gastro-intestinal side effects and induce the expression of inflammatory markers in colon cancer cells. Here, we compared the effects of both CaSR-specific (R enantiomers) and -u...

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Published in: International Journal of Molecular Sciences
ISSN: 1422-0067
Published: MDPI AG 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa58160
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Here, we compared the effects of both CaSR-specific (R enantiomers) and -unspecific (S enantiomers) enantiomers of a calcimimetic (NPS 568) and a calcilytic (allosteric CaSR antagonists; NPS 2143) to prove that these effects are indeed mediated via the CaSR, rather than via off-target effects, e.g., on &#x3B2;-adrenoceptors or calcium channels, of these drugs. The unspecific S enantiomer of NPS 2143 and NPS S-2143 was prepared using synthetic chemistry and characterized using crystallography. NPS S-2143 was then tested in HEK-293 cells stably transfected with the human CaSR (HEK-CaSR), where it did not inhibit CaSR-mediated intracellular Ca2+ signals, as expected. HT29 colon cancer cells transfected with the CaSR were treated with both enantiomers of NPS 568 and NPS 2143 alone or in combination, and the expression of CaSR and the pro-inflammatory cytokine interleukin 8 (IL-8) was measured by RT-qPCR and ELISA. 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spelling 2021-10-25T16:31:38.5675990 v2 58160 2021-09-30 Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells b97beeed16f8e0524551233ade909565 Marcella Bassetto Marcella Bassetto true false 2021-09-30 FGSEN Pharmacological allosteric agonists (calcimimetics) of the extracellular calcium-sensing receptor (CaSR) have substantial gastro-intestinal side effects and induce the expression of inflammatory markers in colon cancer cells. Here, we compared the effects of both CaSR-specific (R enantiomers) and -unspecific (S enantiomers) enantiomers of a calcimimetic (NPS 568) and a calcilytic (allosteric CaSR antagonists; NPS 2143) to prove that these effects are indeed mediated via the CaSR, rather than via off-target effects, e.g., on β-adrenoceptors or calcium channels, of these drugs. The unspecific S enantiomer of NPS 2143 and NPS S-2143 was prepared using synthetic chemistry and characterized using crystallography. NPS S-2143 was then tested in HEK-293 cells stably transfected with the human CaSR (HEK-CaSR), where it did not inhibit CaSR-mediated intracellular Ca2+ signals, as expected. HT29 colon cancer cells transfected with the CaSR were treated with both enantiomers of NPS 568 and NPS 2143 alone or in combination, and the expression of CaSR and the pro-inflammatory cytokine interleukin 8 (IL-8) was measured by RT-qPCR and ELISA. Only the CaSR-selective enantiomers of the calcimimetic NPS 568 and NPS 2143 were able to modulate CaSR and IL-8 expression. We proved that pro-inflammatory effects in colon cancer cells are indeed mediated through CaSR activation. The non-CaSR selective enantiomer NPS S-2143 will be a valuable tool for investigations in CaSR-mediated processes. Journal Article International Journal of Molecular Sciences 22 18 10124 MDPI AG 1422-0067 calcium-sensing receptor; enantiomer; calcimimetic; calcilytic; colon cancer; stereospecificity; HT-29; IL-8; inflammation 19 9 2021 2021-09-19 10.3390/ijms221810124 COLLEGE NANME Science and Engineering - Faculty COLLEGE CODE FGSEN Swansea University Austrian Science Fund (FWF) and the Herzfelder’sche Familienstiftung, grant number P 32840-B (to M.S., Martin Schepelmann); the Austrian Science Fund (FWF), grant number P 29948-B28 (to E.K.); the European Union Horizon 2020 research and innovation programme, grant number 675228 (to E.K.); and the Welsh Government through the Knowledge Economy Skills Scholarship 2, grant number 516062 (to D.R.) 2021-10-25T16:31:38.5675990 2021-09-30T15:15:26.2222120 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Martin Schepelmann 1 Nadja Kupper 2 Marta Sladczyk 3 Bethan Mansfield 4 Teresa Manhardt 5 Karina Piatek 6 Luca Iamartino 7 Daniela Riccardi 8 Benson M. Kariuki 9 Marcella Bassetto 10 Enikö Kallay 11 58160__21059__9dc5c72d70f5400cb2f101d0f177324a.pdf 58160.pdf 2021-09-30T15:16:48.5174542 Output 2874719 application/pdf Version of Record true © 2021 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license true eng https://creativecommons.org/licenses/by/4.0/
title Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells
spellingShingle Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells
Marcella Bassetto
title_short Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells
title_full Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells
title_fullStr Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells
title_full_unstemmed Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells
title_sort Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells
author_id_str_mv b97beeed16f8e0524551233ade909565
author_id_fullname_str_mv b97beeed16f8e0524551233ade909565_***_Marcella Bassetto
author Marcella Bassetto
author2 Martin Schepelmann
Nadja Kupper
Marta Sladczyk
Bethan Mansfield
Teresa Manhardt
Karina Piatek
Luca Iamartino
Daniela Riccardi
Benson M. Kariuki
Marcella Bassetto
Enikö Kallay
format Journal article
container_title International Journal of Molecular Sciences
container_volume 22
container_issue 18
container_start_page 10124
publishDate 2021
institution Swansea University
issn 1422-0067
doi_str_mv 10.3390/ijms221810124
publisher MDPI AG
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
document_store_str 1
active_str 0
description Pharmacological allosteric agonists (calcimimetics) of the extracellular calcium-sensing receptor (CaSR) have substantial gastro-intestinal side effects and induce the expression of inflammatory markers in colon cancer cells. Here, we compared the effects of both CaSR-specific (R enantiomers) and -unspecific (S enantiomers) enantiomers of a calcimimetic (NPS 568) and a calcilytic (allosteric CaSR antagonists; NPS 2143) to prove that these effects are indeed mediated via the CaSR, rather than via off-target effects, e.g., on β-adrenoceptors or calcium channels, of these drugs. The unspecific S enantiomer of NPS 2143 and NPS S-2143 was prepared using synthetic chemistry and characterized using crystallography. NPS S-2143 was then tested in HEK-293 cells stably transfected with the human CaSR (HEK-CaSR), where it did not inhibit CaSR-mediated intracellular Ca2+ signals, as expected. HT29 colon cancer cells transfected with the CaSR were treated with both enantiomers of NPS 568 and NPS 2143 alone or in combination, and the expression of CaSR and the pro-inflammatory cytokine interleukin 8 (IL-8) was measured by RT-qPCR and ELISA. Only the CaSR-selective enantiomers of the calcimimetic NPS 568 and NPS 2143 were able to modulate CaSR and IL-8 expression. We proved that pro-inflammatory effects in colon cancer cells are indeed mediated through CaSR activation. The non-CaSR selective enantiomer NPS S-2143 will be a valuable tool for investigations in CaSR-mediated processes.
published_date 2021-09-19T04:14:28Z
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score 11.021648

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