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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

Englerin A affects proliferation of a subset of cancer cell lines across many cell lineages while englerin B is inactive.(A) Scatterplot of englerin A cell line profiling experiment. (B) Scatterplot of englerin B cell line profiling experiment. Each point represents effect of englerin A or B on growth of a single tumor cell line. Y-axis indicates maximal effect on growth and X-axis indicates potency. Tumor cell line lineage is indicated by color and the legend is in the figure. Englerin A sensitive (circles), englerin A refractory (squares) and englerin A intermediate (diamonds) cell line calls are indicated.
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pone.0127498.g002: Englerin A affects proliferation of a subset of cancer cell lines across many cell lineages while englerin B is inactive.(A) Scatterplot of englerin A cell line profiling experiment. (B) Scatterplot of englerin B cell line profiling experiment. Each point represents effect of englerin A or B on growth of a single tumor cell line. Y-axis indicates maximal effect on growth and X-axis indicates potency. Tumor cell line lineage is indicated by color and the legend is in the figure. Englerin A sensitive (circles), englerin A refractory (squares) and englerin A intermediate (diamonds) cell line calls are indicated.

Mentions: The effect of englerin A and englerin B (Fig 1) on proliferation of 524 cancer cell lines from the cancer cell line encyclopedia (CCLE)[13] was measured in a large scale cell profiling experiment (Fig 2). The scatter plot for englerin A shows that the compound is not generally anti-proliferative but potently blocks growth in a subset of cancer cell lines (Fig 2A). Englerin A sensitive cell lines occur in many different lineages (Table 1) suggesting that a genetic lesion or specific gene/pathway expression may be responsible for sensitivity to englerin A. Englerin B differs from englerin A only by the loss of a glycolate side chain (Fig 1). The englerin B scatter plot (Fig 2B) indicates no cancer cell lines have their growth potently inhibited by this molecule, making englerin B an ideal negative control for englerin A.


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)

Englerin A affects proliferation of a subset of cancer cell lines across many cell lineages while englerin B is inactive.(A) Scatterplot of englerin A cell line profiling experiment. (B) Scatterplot of englerin B cell line profiling experiment. Each point represents effect of englerin A or B on growth of a single tumor cell line. Y-axis indicates maximal effect on growth and X-axis indicates potency. Tumor cell line lineage is indicated by color and the legend is in the figure. Englerin A sensitive (circles), englerin A refractory (squares) and englerin A intermediate (diamonds) cell line calls are indicated.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0127498.g002: Englerin A affects proliferation of a subset of cancer cell lines across many cell lineages while englerin B is inactive.(A) Scatterplot of englerin A cell line profiling experiment. (B) Scatterplot of englerin B cell line profiling experiment. Each point represents effect of englerin A or B on growth of a single tumor cell line. Y-axis indicates maximal effect on growth and X-axis indicates potency. Tumor cell line lineage is indicated by color and the legend is in the figure. Englerin A sensitive (circles), englerin A refractory (squares) and englerin A intermediate (diamonds) cell line calls are indicated.
Mentions: The effect of englerin A and englerin B (Fig 1) on proliferation of 524 cancer cell lines from the cancer cell line encyclopedia (CCLE)[13] was measured in a large scale cell profiling experiment (Fig 2). The scatter plot for englerin A shows that the compound is not generally anti-proliferative but potently blocks growth in a subset of cancer cell lines (Fig 2A). Englerin A sensitive cell lines occur in many different lineages (Table 1) suggesting that a genetic lesion or specific gene/pathway expression may be responsible for sensitivity to englerin A. Englerin B differs from englerin A only by the loss of a glycolate side chain (Fig 1). The englerin B scatter plot (Fig 2B) indicates no cancer cell lines have their growth potently inhibited by this molecule, making englerin B an ideal negative control for englerin A.

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