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

Carson C, Raman P, Tullai J, Xu L, Henault M, Thomas E, Yeola S, Lao J, McPate M, Verkuyl JM, Marsh G, Sarber J, Amaral A, Bailey S, Lubicka D, Pham H, Miranda N, Ding J, Tang HM, Ju H, Tranter P, Ji N, Krastel P, Jain RK, Schumacher AM, Loureiro JJ, George E, Berellini G, Ross NT, Bushell SM, Erdemli G, Solomon JM - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States of America.

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 ┬Čover 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.

No MeSH data available.


Related in: MedlinePlus

Chemical structures of englerin A and englerin B.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4476799&req=5

pone.0127498.g001: Chemical structures of englerin A and englerin B.

Mentions: Natural products are secondary metabolites most commonly isolated from plants and microorganisms. Bioactive natural products are highly evolved chemical species which often bind tightly to their targets to exert their biological activity and have been a rich source of new pharmaceutical compounds[1, 2]. The guaiane sesquiterpene englerin A (Fig 1a) was isolated in 2008 from the bark of the African plant phyllanthus engleri [3]. Its unique chemical structure suggested to us and others[4] that englerin A may bind a novel target. Englerin A is of medicinal interest because it preferentially inhibits growth of renal cell carcinoma (RCC) cell lines in the NCI-60 panel[3] and preferentially inhibits RCC cell line growth relative to gliobastoma, breast, prostate, and non-transformed kidney cells[5, 6]. Englerin A is also attractive to medicinal chemists because it can be synthesized in the laboratory[4, 7].


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

Carson C, Raman P, Tullai J, Xu L, Henault M, Thomas E, Yeola S, Lao J, McPate M, Verkuyl JM, Marsh G, Sarber J, Amaral A, Bailey S, Lubicka D, Pham H, Miranda N, Ding J, Tang HM, Ju H, Tranter P, Ji N, Krastel P, Jain RK, Schumacher AM, Loureiro JJ, George E, Berellini G, Ross NT, Bushell SM, Erdemli G, Solomon JM - PLoS ONE (2015)

Chemical structures of englerin A and englerin B.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476799&req=5

pone.0127498.g001: Chemical structures of englerin A and englerin B.
Mentions: Natural products are secondary metabolites most commonly isolated from plants and microorganisms. Bioactive natural products are highly evolved chemical species which often bind tightly to their targets to exert their biological activity and have been a rich source of new pharmaceutical compounds[1, 2]. The guaiane sesquiterpene englerin A (Fig 1a) was isolated in 2008 from the bark of the African plant phyllanthus engleri [3]. Its unique chemical structure suggested to us and others[4] that englerin A may bind a novel target. Englerin A is of medicinal interest because it preferentially inhibits growth of renal cell carcinoma (RCC) cell lines in the NCI-60 panel[3] and preferentially inhibits RCC cell line growth relative to gliobastoma, breast, prostate, and non-transformed kidney cells[5, 6]. Englerin A is also attractive to medicinal chemists because it can be synthesized in the laboratory[4, 7].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States of America.

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 ┬Čover 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.

No MeSH data available.


Related in: MedlinePlus