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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

Serum stability and pharmacokinetics of englerin A.(A) Levels of englerin A detected after incubation in serum from dog (open square), human (black square), rat (open circle), and mouse (black circle). (B) Pharmacokinetics of englerin A in rats after a single oral dose of 5 mg/kg (mean +/- S.E.M.), englerin A (black circle) and englerin B (open square).
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pone.0127498.g007: Serum stability and pharmacokinetics of englerin A.(A) Levels of englerin A detected after incubation in serum from dog (open square), human (black square), rat (open circle), and mouse (black circle). (B) Pharmacokinetics of englerin A in rats after a single oral dose of 5 mg/kg (mean +/- S.E.M.), englerin A (black circle) and englerin B (open square).

Mentions: In preparation for in vivo studies, the plasma stability of englerin A was studied. Englerin A was stable in plasma from dogs and humans but was unstable in plasma from rats and mice (Fig 7A). There is virtually no englerin A remaining after 90 minutes incubation in rat or mouse plasma. This plasma instability suggested that it may be difficult to achieve significant exposure of englerin A in rodents. To determine the exposure and pharmacokinetic (PK) parameters in rat, an oral dose of englerin A (5 mg/kg) was administered and well tolerated (Table 3). However the levels of englerin A detected in blood never exceeded 12 nM (Fig 7B). Interestingly, higher blood levels of englerin B were observed (>50 nM) after dosing englerin A, suggesting that the rapid metabolism or plasma instability seen in vitro is recapitulated in vivo (Fig 7B). Conversion of englerin A into englerin B can occur through cleavage of the glycolate group. It is known that rodents have high levels of plasma esterases [25] which may explain the instability of englerin A in plasma from rats and mice.


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)

Serum stability and pharmacokinetics of englerin A.(A) Levels of englerin A detected after incubation in serum from dog (open square), human (black square), rat (open circle), and mouse (black circle). (B) Pharmacokinetics of englerin A in rats after a single oral dose of 5 mg/kg (mean +/- S.E.M.), englerin A (black circle) and englerin B (open square).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0127498.g007: Serum stability and pharmacokinetics of englerin A.(A) Levels of englerin A detected after incubation in serum from dog (open square), human (black square), rat (open circle), and mouse (black circle). (B) Pharmacokinetics of englerin A in rats after a single oral dose of 5 mg/kg (mean +/- S.E.M.), englerin A (black circle) and englerin B (open square).
Mentions: In preparation for in vivo studies, the plasma stability of englerin A was studied. Englerin A was stable in plasma from dogs and humans but was unstable in plasma from rats and mice (Fig 7A). There is virtually no englerin A remaining after 90 minutes incubation in rat or mouse plasma. This plasma instability suggested that it may be difficult to achieve significant exposure of englerin A in rodents. To determine the exposure and pharmacokinetic (PK) parameters in rat, an oral dose of englerin A (5 mg/kg) was administered and well tolerated (Table 3). However the levels of englerin A detected in blood never exceeded 12 nM (Fig 7B). Interestingly, higher blood levels of englerin B were observed (>50 nM) after dosing englerin A, suggesting that the rapid metabolism or plasma instability seen in vitro is recapitulated in vivo (Fig 7B). Conversion of englerin A into englerin B can occur through cleavage of the glycolate group. It is known that rodents have high levels of plasma esterases [25] which may explain the instability of englerin A in plasma from rats and mice.

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