TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A
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Sin Ying Cheung1, Matthias Henrot2, Mohammad Al-Saad3, Matthias Baumann4, Heiko Muller4, Anke Unger4, Hussein N. Rubaiy1, Ilka Mathar5, Klaus Dinkel4, Peter Nussbaumer4, Bert Klebl4, Marc Freichel5, Baptiste Rode1, Sebastian Trainor1, Steven J. Clapcote3, Mathias Christmann2, Herbert Waldmann6,7, Syed Khawar Abbas1, David J. Beech1 and Naveen S. Vasudev1
1School of Medicine, University of Leeds, Leeds, LS2 9JT, England, UK
2Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
3School of Biomedical Sciences, University of Leeds, Leeds, LS2 9JT, UK
4Lead Discovery Center GmbH, D-44227 Dortmund, Germany
5Institute of Pharmacology, Universität Heidelberg, D-69120 Heidelberg, Germany
6Max-Planck-Institut für Molekulare Physiologie, D-44227 Dortmund, Germany
7Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, D-44227 Dortmund, Germany
Naveen S. Vasudev, email: firstname.lastname@example.org
David J. Beech, email: D.J.Beech@leeds.ac.uk
Keywords: TRPC4 channels; TRPC5 channels; renal cancer; breast cancer; Ewing’s sarcoma
Received: September 29, 2017 Accepted: May 01, 2018 Published: July 03, 2018
(-)-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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