2. Academic Validation
  3. Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation

Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation

  • PLoS One. 2015 Jun 22;10(6):e0127498. doi: 10.1371/journal.pone.0127498.
Cheryl Carson 1,  Pichai Raman 1,  Jennifer Tullai 1,  Lei Xu 1,  Martin Henault 1,  Emily Thomas 1,  Sarita Yeola 1,  Jianmin Lao 2,  Mark McPate 3,  J Martin Verkuyl 3,  George Marsh 1,  Jason Sarber 1,  Adam Amaral 1,  Scott Bailey 1,  Danuta Lubicka 1,  Helen Pham 1,  Nicolette Miranda 1,  Jian Ding 1,  Hai-Ming Tang 4,  Haisong Ju 4,  Pamela Tranter 3,  Nan Ji 1,  Philipp Krastel 5,  Rishi K Jain 1,  Andrew M Schumacher 2,  Joseph J Loureiro 1,  Elizabeth George 1,  Giuliano Berellini 1,  Nathan T Ross 1,  Simon M Bushell 1,  Gül Erdemli 1,  Jonathan M Solomon 1
Affiliations

Affiliations

  • 1 Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States of America.
  • 2 Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
  • 3 Novartis Institutes for Biomedical Research, Horsham, United Kingdom.
  • 4 Novartis Institutes for Biomedical Research, East Hanover, New Jersey, United States of America.
  • 5 Novartis Institutes for Biomedical Research, Basel, Switzerland.
PMID: 26098886 DOI: 10.1371/journal.pone.0127498
Abstract

Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of englerin A on ¬over 500 well characterized Cancer cell lines showed that englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for englerin A. Genetic experiments demonstrate that TRPC4 expression is both necessary and sufficient for englerin A induced growth inhibition. Englerin A induces calcium influx and membrane depolarization in cells expressing high levels of TRPC4 or its close ortholog TRPC5. Electrophysiology experiments confirmed that englerin A is a TRPC4 agonist. Both the englerin A induced current and the englerin A induced growth inhibition can be blocked by the TRPC4/C5 inhibitor ML204. These experiments confirm that activation of TRPC4/C5 channels inhibits tumor cell line proliferation and confirms the TRPC4 target hypothesis generated by the cell line profiling. In selectivity assays englerin A weakly inhibits TRPA1, TRPV3/V4, and TRPM8 which suggests that englerin A may bind a common feature of TRP ion channels. In vivo experiments show that englerin A is lethal in rodents near doses needed to activate the TRPC4 channel. This toxicity suggests that englerin A itself is probably unsuitable for further drug development. However, since englerin A can be synthesized in the laboratory, it may be a useful chemical starting point to identify novel modulators of other TRP family channels.

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