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TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A

(-)-Englerin A (EA) is a natural product which has potent cytotoxic effects on renal cell carcinoma cells and other types of cancer cell but not non-cancer cells. Although selectively cytotoxic to cancer cells, adverse reaction in mice and rats has been suggested. EA is a remarkably potent activator...

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Autores principales: Cheung, Sin Ying, Henrot, Matthias, Al-Saad, Mohammad, Baumann, Matthias, Muller, Heiko, Unger, Anke, Rubaiy, Hussein N., Mathar, Ilka, Dinkel, Klaus, Nussbaumer, Peter, Klebl, Bert, Freichel, Marc, Rode, Baptiste, Trainor, Sebastian, Clapcote, Steven J., Christmann, Mathias, Waldmann, Herbert, Abbas, Syed Khawar, Beech, David J., Vasudev, Naveen S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049859/
https://www.ncbi.nlm.nih.gov/pubmed/30038709
http://dx.doi.org/10.18632/oncotarget.25659
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author Cheung, Sin Ying
Henrot, Matthias
Al-Saad, Mohammad
Baumann, Matthias
Muller, Heiko
Unger, Anke
Rubaiy, Hussein N.
Mathar, Ilka
Dinkel, Klaus
Nussbaumer, Peter
Klebl, Bert
Freichel, Marc
Rode, Baptiste
Trainor, Sebastian
Clapcote, Steven J.
Christmann, Mathias
Waldmann, Herbert
Abbas, Syed Khawar
Beech, David J.
Vasudev, Naveen S.
author_facet Cheung, Sin Ying
Henrot, Matthias
Al-Saad, Mohammad
Baumann, Matthias
Muller, Heiko
Unger, Anke
Rubaiy, Hussein N.
Mathar, Ilka
Dinkel, Klaus
Nussbaumer, Peter
Klebl, Bert
Freichel, Marc
Rode, Baptiste
Trainor, Sebastian
Clapcote, Steven J.
Christmann, Mathias
Waldmann, Herbert
Abbas, Syed Khawar
Beech, David J.
Vasudev, Naveen S.
author_sort Cheung, Sin Ying
collection PubMed
description (-)-Englerin A (EA) is a natural product which has potent cytotoxic effects on renal cell carcinoma cells and other types of cancer cell but not non-cancer cells. Although selectively cytotoxic to cancer cells, adverse reaction in mice and rats has been suggested. EA is a remarkably potent activator of ion channels formed by Transient Receptor Potential Canonical 4 and 5 proteins (TRPC4 and TRPC5) and TRPC4 is essential for EA-mediated cancer cell cytotoxicity. Here we specifically investigated the relevance of TRPC4 and TRPC5 to the adverse reaction. Injection of EA (2 mg.kg(-1) i.p.) adversely affected mice for about 1 hour, manifesting as a marked reduction in locomotor activity, after which they fully recovered. TRPC4 and TRPC5 single knockout mice were partially protected and double knockout mice fully protected. TRPC4/TRPC5 double knockout mice were also protected against intravenous injection of EA. Importance of TRPC4/TRPC5 channels was further suggested by pre-administration of Compound 31 (Pico145), a potent and selective small-molecule inhibitor of TRPC4/TRPC5 channels which did not cause adverse reaction itself but prevented adverse reaction to EA. EA was detected in the plasma but not the brain and so peripheral mechanisms were implicated but not identified. The data confirm the existence of adverse reaction to EA in mice and suggest that it depends on a combination of TRPC4 and TRPC5 which therefore overlaps partially with TRPC4-dependent cancer cell cytotoxicity. The underlying nature of the observed adverse reaction to EA, as a consequence of TRPC4/TRPC5 channel activation, remains unclear and warrants further investigation.
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spelling pubmed-60498592018-07-23 TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A Cheung, Sin Ying Henrot, Matthias Al-Saad, Mohammad Baumann, Matthias Muller, Heiko Unger, Anke Rubaiy, Hussein N. Mathar, Ilka Dinkel, Klaus Nussbaumer, Peter Klebl, Bert Freichel, Marc Rode, Baptiste Trainor, Sebastian Clapcote, Steven J. Christmann, Mathias Waldmann, Herbert Abbas, Syed Khawar Beech, David J. Vasudev, Naveen S. Oncotarget Research Paper (-)-Englerin A (EA) is a natural product which has potent cytotoxic effects on renal cell carcinoma cells and other types of cancer cell but not non-cancer cells. Although selectively cytotoxic to cancer cells, adverse reaction in mice and rats has been suggested. EA is a remarkably potent activator of ion channels formed by Transient Receptor Potential Canonical 4 and 5 proteins (TRPC4 and TRPC5) and TRPC4 is essential for EA-mediated cancer cell cytotoxicity. Here we specifically investigated the relevance of TRPC4 and TRPC5 to the adverse reaction. Injection of EA (2 mg.kg(-1) i.p.) adversely affected mice for about 1 hour, manifesting as a marked reduction in locomotor activity, after which they fully recovered. TRPC4 and TRPC5 single knockout mice were partially protected and double knockout mice fully protected. TRPC4/TRPC5 double knockout mice were also protected against intravenous injection of EA. Importance of TRPC4/TRPC5 channels was further suggested by pre-administration of Compound 31 (Pico145), a potent and selective small-molecule inhibitor of TRPC4/TRPC5 channels which did not cause adverse reaction itself but prevented adverse reaction to EA. EA was detected in the plasma but not the brain and so peripheral mechanisms were implicated but not identified. The data confirm the existence of adverse reaction to EA in mice and suggest that it depends on a combination of TRPC4 and TRPC5 which therefore overlaps partially with TRPC4-dependent cancer cell cytotoxicity. The underlying nature of the observed adverse reaction to EA, as a consequence of TRPC4/TRPC5 channel activation, remains unclear and warrants further investigation. Impact Journals LLC 2018-07-03 /pmc/articles/PMC6049859/ /pubmed/30038709 http://dx.doi.org/10.18632/oncotarget.25659 Text en Copyright: © 2018 Cheung et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Cheung, Sin Ying
Henrot, Matthias
Al-Saad, Mohammad
Baumann, Matthias
Muller, Heiko
Unger, Anke
Rubaiy, Hussein N.
Mathar, Ilka
Dinkel, Klaus
Nussbaumer, Peter
Klebl, Bert
Freichel, Marc
Rode, Baptiste
Trainor, Sebastian
Clapcote, Steven J.
Christmann, Mathias
Waldmann, Herbert
Abbas, Syed Khawar
Beech, David J.
Vasudev, Naveen S.
TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A
title TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A
title_full TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A
title_fullStr TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A
title_full_unstemmed TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A
title_short TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A
title_sort trpc4/trpc5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-englerin a
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049859/
https://www.ncbi.nlm.nih.gov/pubmed/30038709
http://dx.doi.org/10.18632/oncotarget.25659
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