Development of Novel EDG3 Antagonists Using a 3D Database Search and Their Structure−Activity Relationships

Koide, Yoshinobu; Hasegawa, Takeshi; Takahashi, Atsuo; Endo, Akira; Mochizuki, Naoki; Nakagawa, Masako; Nishida, Atsushi

doi:10.1021/jm020080c

Cited by 83 publications

(54 citation statements)

References 38 publications

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“…In 2002, it was reported from a screening of HeLa cells that a single high concentration of BML-241 (10 mM) inhibited the S1P 3 -induced [Ca 2 þ ] i response by 37%, whereas S1P 1 -induced responses were not affected (Koide et al, 2002). Based upon these data, BML-241 was proposed as a lead compound to develop a selective antagonist of the S1P 3 receptor.…”

Section: Discussionmentioning

confidence: 99%

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BML‐241 fails to display selective antagonism at the sphingosine‐1‐phosphate receptor, S1P₃

Jongsma

Hendriks-Balk

Michel

et al. 2006

British J Pharmacology

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Background and purpose: The thiazolidine carboxylic acid, BML-241, has been proposed as a lead compound in development of selective antagonists at the sphingosine-1-phosphate receptor (S1P 3 ), based on its inhibition of the rise in intracellular calcium concentrations ([Ca 2 þ ] i ) in HeLa cells overexpressing S1P receptors. We have studied the antagonistic properties of BML-241 for the S1P 3 receptor in more detail. Experimental approach: Chinese hamster ovary (CHO) cells stably transfected with the S1P 3 , S1P 2 or a 1A -adrenoceptors were used to investigate the effect of BML-241 on increases in [Ca 2 þ ] i mediated via different receptors. CHO-K1 cells were used to study ATP-induced [Ca 2 þ ] i elevations. Effects on S1P 3 -mediated inhibition of forskolin-induced cAMP accumulation and on binding to a 1A -adrenoceptors were also investigated. In addition, the effect of BML-241 on contractions of rat mesenteric artery induced by phenylephrine was studied in an organ bath. Key results: High concentrations of BML-241 (10 mM) inhibited the rise in [Ca 2 þ ] i induced by S1P 3 and S1P 2 receptor stimulation; lower concentrations were ineffective. This high concentration of BML-241 also inhibited [Ca 2 þ ] i increases via P2 (nucleotide) receptor or a 1A -adrenoceptor stimulation. Moreover, BML-241 (10 mM) inhibited a 1 -adrenoceptor-mediated contraction of rat mesenteric artery but did not displace [3 H]-prazosin from a 1A -adrenoceptors in concentrations up to 100 mM. BML-241 (10 mM) did not affect the S1P 3 -mediated decrease of forskolin-induced cAMP accumulation. Conclusions and Implications: We conclude that BML-241 is a low potency, non-selective inhibitor of increases in [Ca 2 þ ] i , rather than a specific antagonist at the S1P 3 receptor.

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Section: Discussionmentioning

confidence: 99%

“…This compound was proposed as a lead compound in developing selective antagonists of the S1P 3 receptor (Koide et al, 2002). However, those conclusions were based on the measurements with one BML-241 concentration and on the comparison of only the S1P 1 and S1P 3 receptor in one assay.…”

Section: Introductionmentioning

confidence: 99%

BML‐241 fails to display selective antagonism at the sphingosine‐1‐phosphate receptor, S1P₃

Jongsma

Hendriks-Balk

Michel

et al. 2006

British J Pharmacology

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“…The identity of the S1P receptor involved in regulating the ERK-1/2 pathway was evaluated using pharmacological agents that demonstrate selectivity at S1P receptors. We used JTE013, which is reported to be an S1P 2 -selective antagonist (28), and CAY10444 (29), which is an S1P 3 antagonist. To further characterize the pharmacological specificity of JTE013 and CAY10444, we used HTC4 cells in which S1P 2,3,4 were separately stably expressed, and intracellu- lar calcium mobilization was measured using the Fura-2 indicator dye.…”

Section: Mda-mb-453 Cells Are Her2mentioning

confidence: 99%

Sphingosine 1-Phosphate Receptor 4 Uses HER2 (ERBB2) to Regulate Extracellular Signal Regulated Kinase-1/2 in MDA-MB-453 Breast Cancer Cells

Long

Fujiwara

Edwards

et al. 2010

Journal of Biological Chemistry

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We demonstrate here that the bioactive lipid sphingosine 1-phosphate (S1P) uses sphingosine 1-phosphate receptor 4 (S1P 4 ) and human epidermal growth factor receptor 2 (HER2) to stimulate the extracellular signal regulated protein kinase 1/2 (ERK-1/2) pathway in MDA-MB-453 cells. This was based on several lines of evidence. First, the S1P stimulation of ERK-1/2 was abolished by JTE013, which we show here is an S1P 2/4 antagonist and reduced by siRNA knockdown of S1P 4 . Second, the S1P-stimulated activation of ERK-1/2 was almost completely abolished by a HER2 inhibitor (ErbB2 inhibitor II) and reduced by siRNA knockdown of HER2 expression. Third, phyto-S1P, which is an S1P 4 agonist, stimulated ERK-1/2 activation in an S1P 4 -and HER2-dependent manner. Fourth, FTY720 phosphate, which is an agonist at S1P 1,3,4,5 but not S1P 2 stimulated activation of ERK-1/2. Fifth, S1P stimulated the tyrosine phosphorylation of HER2, which was reduced by JTE013. HER2 which is an orphan receptor tyrosine kinase is the preferred dimerization partner of the EGF receptor. However, EGF-stimulated activation of ERK-1/2 was not affected by siRNA knockdown of HER2 or by ErbB2 (epidermal growth factor receptor 2 (or HER2)) inhibitor II in MDA-MB-453 cells. Moreover, S1P-stimulated activation of ERK-1/2 does not require an EGF receptor. Thus, S1P and EGF function in a mutually exclusive manner. In conclusion, the magnitude of the signaling gain on the ERK-1/2 pathway produced in response to S1P can be increased by HER2 in MDA-MB-453 cells. The linkage of S1P with an oncogene suggests that S1P and specifically S1P 4 may have an important role in breast cancer progression.There is increasing evidence that suggests a role for the bioactive lipid sphingosine 1-phosphate (S1P) 2 in breast cancer. S1P binds to a family of five GPCR, termed S1P n (where n ϭ 1-5), that are differentially coupled to heterotrimeric G proteins (G i , G q , and G 12/13 ) to regulate various effectors such as MAP kinases linked to diverse cellular processes such as proliferation, cell survival, and differentiation (1-13). The specificity of signaling in terms of which kinase modules are activated is dependent upon the receptor sub-type involved and is cell context-specific. S1P is produced by the enzyme sphingosine kinase (SK), which catalyzes the phosphorylation of sphingosine to produce S1P. SK (which exists as two isoforms termed SK1 and SK2) is activated by agonists such as antigen, plateletderived growth factor, nerve growth factor, tumor necrosis factor ␣, and epidermal growth factor (EGF), resulting in an increase in intracellular S1P. SK1 activation and/or translocation is regulated by phosphorylation catalyzed by ERK-1/2 and by CIB1 (calcium and integrin-binding protein 1) (14,15). S1P has an important role in breast cancer cells in terms of regulating survival, proliferation, and migration (16 -18). For instance, ectopic expression of SK1 increased S1P levels, estrogen-dependent tumorigenesis, and blocked apoptosis of MCF-7 cells induced by anticancer drug...

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“…7B, treatment of HASMCs with PTX (100 ng/ml) had no effects on hyperglycemiainduced anti-apoptotic effects. Moreover, treatment of HASMCs with VPC23019 (10 mol/l), a selective S1P1/S1P 3 receptor antagonist (35), also did not impact hyperglycemia-induced anti-apoptotic effects. In contrast to S1P, dihydro-S1P, which is structurally similar to S1P and binds to and activates S1P 2 and S1P 5 , had no effects on the serum withdrawal-induced apoptosis in HASMCs (Fig.…”

Section: Resultsmentioning

confidence: 93%

Activation of Sphingosine Kinase-1 Mediates Inhibition of Vascular Smooth Muscle Cell Apoptosis by Hyperglycemia

et al. 2007

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Vascular smooth muscle cell (VSMC) apoptosis plays an essential role in vascular development and atherosclerosis. Hyperglycemia inhibits VSMC apoptosis, which may contribute to the development of diabetic vasculopathy. In the present study, we analyzed the mechanism of high-glucoseinduced anti-apoptotic effect in cultured human aortic smooth muscle cells (HASMCs). Compared with normoglycemia, exposure of HASMCs to hyperglycemia but not mannitol significantly increased sphingosine kinase 1 (SK1) activity but not SK2 activity. This increase was inhibited by protein kinase C (PKC) inhibitor GF109203X, the antioxidant N-acetylcysteine, and the reduced form of glutathione. The mechanism of SK1 activation by high glucose involves plasma membrane translocation. In addition, hyperglycemia markedly inhibited serum withdrawalinduced apoptosis in HASMCs. Importantly, inhibition of SK1 by either a competitive inhibitor N,N-dimethylsphingosine or expression of dominant-negative mutant of SK1(G82D) or specific small interference RNA knockdown substantially attenuated hyperglycemia-induced anti-apoptotic effect and anti-apoptotic protein Bcl-2 expression in HASMCs. Moreover, SK1-mediated anti-apoptotic effect requires the intracellular effects of sphingosine-1-phosphate. We conclude that hyperglycemia stimulates SK1 activity via PKC-and oxidative stress-dependent pathways, leading to decreased apoptosis in HASMCs. Taken together, these observations have important implications for understanding the roles of the SK1 signaling pathway in the pathogenesis of diabetic vasculopathy. Diabetes

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Development of Novel EDG3 Antagonists Using a 3D Database Search and Their Structure−Activity Relationships

Cited by 83 publications

References 38 publications

BML‐241 fails to display selective antagonism at the sphingosine‐1‐phosphate receptor, S1P₃

BML‐241 fails to display selective antagonism at the sphingosine‐1‐phosphate receptor, S1P₃

Sphingosine 1-Phosphate Receptor 4 Uses HER2 (ERBB2) to Regulate Extracellular Signal Regulated Kinase-1/2 in MDA-MB-453 Breast Cancer Cells

Activation of Sphingosine Kinase-1 Mediates Inhibition of Vascular Smooth Muscle Cell Apoptosis by Hyperglycemia

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Development of Novel EDG3 Antagonists Using a 3D Database Search and Their Structure−Activity Relationships

Cited by 83 publications

References 38 publications

BML‐241 fails to display selective antagonism at the sphingosine‐1‐phosphate receptor, S1P3

BML‐241 fails to display selective antagonism at the sphingosine‐1‐phosphate receptor, S1P3

Sphingosine 1-Phosphate Receptor 4 Uses HER2 (ERBB2) to Regulate Extracellular Signal Regulated Kinase-1/2 in MDA-MB-453 Breast Cancer Cells

Activation of Sphingosine Kinase-1 Mediates Inhibition of Vascular Smooth Muscle Cell Apoptosis by Hyperglycemia

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BML‐241 fails to display selective antagonism at the sphingosine‐1‐phosphate receptor, S1P₃

BML‐241 fails to display selective antagonism at the sphingosine‐1‐phosphate receptor, S1P₃