title: (-)-Englerin A is a potent and selective activator of TRPC4 and TRPC5 calcium channels.
abstract: Current therapies for common types of cancer such as renal cell cancer are often ineffective and unspecific, and novel pharmacological targets and approaches are in high demand. Here we show the unexpected possibility for the rapid and selective killing of renal cancer cells through activation of calcium-permeable nonselective transient receptor potential canonical (TRPC) calcium channels by the sesquiterpene (-)-englerin A. This compound was found to be a highly efficient, fast-acting, potent, selective, and direct stimulator of TRPC4 and TRPC5 channels. TRPC4/5 activation through a high-affinity extracellular (-)-englerin A binding site may open up novel opportunities for drug discovery aimed at renal cancer.
authors.affiliation: Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany); Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany).
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Akbulut
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Gaunt
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Muraki
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Ludlow
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Amer
authors.forename: Alexander
authors.initials: A
authors.lastname: Bruns
authors.forename: Naveen S
authors.initials: NS
authors.lastname: Vasudev
authors.forename: Lea
authors.initials: L
authors.lastname: Radtke
authors.forename: Matthieu
authors.initials: M
authors.lastname: Willot
authors.forename: Sven
authors.initials: S
authors.lastname: Hahn
authors.forename: Tobias
authors.initials: T
authors.lastname: Seitz
authors.forename: Slava
authors.initials: S
authors.lastname: Ziegler
authors.forename: Mathias
authors.initials: M
authors.lastname: Christmann
authors.forename: David J
authors.initials: DJ
authors.lastname: Beech
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D045789:Sesquiterpenes, Guaiane / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D050052:TRPC Cation Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D045789:Sesquiterpenes, Guaiane; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; C491780:TRPC5 protein, human; C534971:englerin A; D002118:Calcium
keywords: antitumor agents; calcium ions; ion channels; natural products