Pharmacological Characterization of a Novel Sulfonylureid-Pyrazole Derivative, SM-19712, a Potent Nonpeptidic Inhibitor of Endothelin Converting Enzyme

Umekawa, Kayo; Hasegawa, Hirohiko; Tsutsumi, Yoshitaka; Sato, Kimihiko; Matsumura, Yasuo; Ohashi, Naohito

doi:10.1254/jjp.84.7

Cited by 34 publications

(31 citation statements)

References 38 publications

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“…Our study demonstrates that a specific inhibitor of ECE-1 46 can inhibit proliferation of oral SCC cells. The same inhibitor has been reported to inhibit the invasion of prostate cancer (PC) cells.…”

Section: Discussionmentioning

confidence: 58%

“…Furthermore, cells seeded with 10 4 cells per well in DMEM/ F12 supplemented with 10% FCS and P/S in a separate plate were incubated for 24 hr and then for further 24 hr in DMEM/F12 with 2% FCS supplemented with increasing concentrations (10 nM, 100 nM or 1 lM) of 4-chloro-N-[[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]-carbonyl]benzene sulphonamide monosodium salt, referred to here as ECE-i, which is a specific inhibitor of ECE-1 and characterised by Umekawa et al 46 Cell proliferation was determined using the rapid cell proliferation kit (ONCOGENE TM Research Products, San Diego, CA), according to the manufacturer's instructions.…”

Section: Analyses Of Cell Proliferationmentioning

confidence: 99%

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Endothelin system in oral squamous carcinoma cells: Specific siRNA targeting of ECE‐1 blocks cell proliferation

Awano

Dawson

Hunter

et al. 2005

Intl Journal of Cancer

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The present study focused on the endothelin axis in human oral squamous cell carcinoma (SCC) cells. We investigated the expression and distribution of endothelin-1 (ET-1), its receptors (endothelin-A receptor (ET A R) and endothelin-B receptor (ET B R)) and isoforms of its specific converting enzyme 1b, 1c) and the report on their relative influences on cell proliferation. We also investigated the effect of an ECE-specific inhibitor (ECE-i) and siRNA targeting of the ECE-1 gene on SCC cell proliferation. We observed the expression of ET-1, ET A R, ET B R and all endothelin-converting enzyme-1 (ECE-1) isoforms in oral SCC cells, but only the expression of ET-1, ET B R and ECE-1 was increased when compared to normal human epidermal keratinocytes. ET-1 alone stimulated proliferation of oral SCC cells. Antagonists of either ET A R or ET B R inhibited ET-1-mediated proliferation. Decreased ECE-1 expression after ECE siRNA treatment reduced SCC cell proliferation. Antiproliferative effects were also observed by inhibiting ECE activity with ECE-i. In conclusion, the present study demonstrates that modulation of the endothelin system in oral SCC cells might provide a novel therapeutic protocol for oral cancer. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 58%

Section: Analyses Of Cell Proliferationmentioning

confidence: 99%

Endothelin system in oral squamous carcinoma cells: Specific siRNA targeting of ECE‐1 blocks cell proliferation

Awano

Dawson

Hunter

et al. 2005

Intl Journal of Cancer

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“…Peptides and thiorphan were purchased from Sigma. The ECE-1 specific inhibitor, 4-chloro-N-[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]-carbonyl]benzene sulphonamide monosodium salt, referred to here as ECE-i, was described and characterised by Umekawa et al (2000). Endothelin-1 was obtained from The Peptide Institute (Barnet, UK).…”

Section: Methodsmentioning

confidence: 99%

Stromal–epithelial interactions influence prostate cancer cell invasion by altering the balance of metallopeptidase expression

et al. 2004

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Perturbations of stromal -epithelial interactions in the developing tumour can contribute to cancer invasion and metastasis. The structurally related metallopeptidases endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP) contribute sequentially to the synthesis and inactivation of ET-1, a mitogenic peptide that has been shown to affect tumour behaviour. This study has investigated the interaction between metastatic tumour epithelial cells, which lack NEP, and stromal cells, which we have shown to express ECE-1 (stromal -epithelial interactions), using Matrigel invasion chambers. The epithelial cell lines utilised in this study include androgen-sensitive LNCaP, androgen-independent PC-3, Du145 and recently established PNT-1a, PNT2-C2 and P4E6 prostate cell lines. Specific inhibition of endogenous ECE-1 activity in stromal cells reduced PC-3 and Du145 invasion by 70 and 50%, respectively. Addition of recombinant NEP to inactivate endogenous mitogenic peptides resulted in 50 and 20% reductions in invasion in PC-3 and Du145 cells, respectively. Neutral endopeptidase effects were reversed in the presence of thiorphan, a specific NEP inhibitor. Supplementation of defined media with bradykinin and ET-1 significantly increased PC-3 invasion by 40 and 50%, respectively. Du145 cell invasion increased by approximately 100% on adding ET-1. These studies implicate the metallopeptidases NEP and ECE-1 as mediators of prostate cancer invasion via a stromal/epithelial interaction.

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“…Second, SM-19712 caused markedly sustained ERK2 activation, whereas overexpression of ECE-1c attenuated ERK2 activation. A second ECE-1 inhibitor, PD-069185, also caused prolonged ERK2 activation, although the effect was less pronounced, probably because PD-069185 is not membrane permeant (19), whereas SM-19712 is a membrane permeable inhibitor (29). Third, the H ϩ -ATPase inhibitor bafilomycin A 1 , which prevents endosomal acidification and inhibits ECE-1-dependent SP degradation in endosomes (13), also caused sustained ERK activation.…”

Section: Ece-1 Degrades Sp In Endosomes Andmentioning

confidence: 98%

Endosomal Endothelin-converting Enzyme-1

Cottrell

Padilla

Amadesi

et al. 2009

Journal of Biological Chemistry

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Neuropeptide signaling at the cell surface is regulated by metalloendopeptidases, which degrade peptides in the extracellular fluid, and ␤-arrestins, which interact with G protein-coupled receptors (GPCRs) to mediate desensitization. ␤-Arrestins also recruit GPCRs and mitogen-activated protein kinases to endosomes to allow internalized receptors to continue signaling, but the mechanisms regulating endosomal signaling are unknown. We report that endothelin-converting enzyme-1 (ECE-1) degrades substance P (SP) in early endosomes of epithelial cells and neurons to destabilize the endosomal mitogen-activated protein kinase signalosome and terminate signaling. ECE-1 inhibition caused endosomal retention of the SP neurokinin 1 receptor, ␤-arrestins, and Src, resulting in markedly sustained ERK2 activation in the cytosol and nucleus, whereas ECE-1 overexpression attenuated ERK2 activation. ECE-1 inhibition also enhanced SP-induced expression and phosphorylation of the nuclear death receptor Nur77, resulting in cell death. Thus, endosomal ECE-1 attenuates ERK2-mediated SP signaling in the nucleus to prevent cell death. We propose that agonist availability in endosomes, here regulated by ECE-1, controls ␤-arrestin-dependent signaling of endocytosed GPCRs.Signal transduction at the plasma membrane is tightly regulated by well characterized mechanisms. For the large family of G protein-coupled receptors (GPCRs), 2 regulation of extracellular agonist concentration and receptor coupling to heterotrimeric G proteins control signal transduction. Cell-surface metalloendopeptidases, exemplified by neprilysin, degrade neuropeptides in the extracellular fluid to regulate receptor activation (1, 2). G protein receptor kinases phosphorylate activated GPCRs to promote their interaction with ␤-arrestins, which uncouple receptors from G proteins and mediate desensitization (3). However, activated GPCRs internalize, and endocytosed receptors continue to signal by G protein-independent mechanisms. ␤-Arrestins mediate endocytosis and intracellular signaling of GPCRs. ␤-Arrestins couple GPCRs to clathrin and AP2 to mediate endocytosis (4, 5) and are scaffolds that recruit Src, Raf-1, and mitogen-activated protein kinases (MAPKs) to GPCRs in endosomes forming a MAPK signalosome, which determines the location and function of activated extracellular signal-regulated kinases (ERKs) (6 -9). Compared with our understanding of receptor regulation at the plasma membrane, little is known about the mechanisms that regulate GPCR signaling and trafficking at the endosomal membrane. Specifically, it is not known whether agonist interaction with GPCRs or GPCR interaction with ␤-arrestins is necessary for receptor signaling in endosomes. Regulation of these interactions could determine the duration of ␤-arrestin-mediated ERK activation, with important functional implications (10, 11). We hypothesized that mechanisms that regulate GPCRs at the plasma membrane also control receptor signaling and trafficking at the endosomal membrane. We recently reported t...

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Pharmacological Characterization of a Novel Sulfonylureid-Pyrazole Derivative, SM-19712, a Potent Nonpeptidic Inhibitor of Endothelin Converting Enzyme

Cited by 34 publications

References 38 publications

Endothelin system in oral squamous carcinoma cells: Specific siRNA targeting of ECE‐1 blocks cell proliferation

Endothelin system in oral squamous carcinoma cells: Specific siRNA targeting of ECE‐1 blocks cell proliferation

Stromal–epithelial interactions influence prostate cancer cell invasion by altering the balance of metallopeptidase expression

Endosomal Endothelin-converting Enzyme-1

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