Inhibitory effect of a prostaglandin E receptor subtype EP1 selective antagonist, ONO-8713, on development of azoxymethane-induced aberrant crypt foci in mice

Watanabe, Kouji; Kawamori, Toshihiko; Nakatsugi, Seiichi; Ohta, Toshihisa; Ohuchida, Shuichi; Yamamoto, Hiroshi; Maruyama, Takayuki; Kondo, Kazuaki; Narumiya, Shuh; Sügimura, Takashi; Wakabayashi, Keiji

doi:10.1016/s0304-3835(00)00440-7

Cited by 114 publications

(66 citation statements)

References 14 publications

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“…In brief, ONO-8713 exhibited a K i value of 0.3 nM for both mouse and human forms of the EP1 receptor and more than 1000 nM for all other types of prostanoid receptors. This compound inhibited PGE2-induced calcium rise with IC50 values of 0.46 and 0.14 M in mouse and human EP1-expressing cells, respectively, but showed no agonistic or antagonistic actions on other types of prostanoid receptors (18).…”

Section: Induction Of Diabetes and Drug Treatmentmentioning

confidence: 88%

“…Selectivity of ONO-8713 as to binding affinity and agonistic and antagonistic activities against PG receptors and thromboxane A2 receptor has been described elsewhere (18). In brief, ONO-8713 exhibited a K i value of 0.3 nM for both mouse and human forms of the EP1 receptor and more than 1000 nM for all other types of prostanoid receptors.…”

Section: Induction Of Diabetes and Drug Treatmentmentioning

confidence: 94%

“…On the basis of the structures of known prostanoid receptor ligands, we performed an extensive screening to identify and optimize a selective EP1 antagonist, and found ONO-8713 (18). Selectivity of ONO-8713 as to binding affinity and agonistic and antagonistic activities against PG receptors and thromboxane A2 receptor has been described elsewhere (18).…”

Section: Induction Of Diabetes and Drug Treatmentmentioning

confidence: 99%

“…Diabetic rats (n ϭ 57) and controls (n ϭ 12) were assigned randomly to treated or untreated groups. A group of diabetic rats (n ϭ 20) was given a selective EP1 antagonist ONO-8713 (Ono Pharmaceutical, Osaka, Japan) at 1000 ppm in regular chow (18). Another group of diabetic rats (n ϭ 17) was given aspirin (Nacalai Tesque, Kyoto, Japan) added to the drinking water at 1.5 mg/ml (12).…”

Section: Induction Of Diabetes and Drug Treatmentmentioning

confidence: 99%

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Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

Makino¹,

Tanaka²,

Mukoyama³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Local production of prostaglandins (PGs) in the kidney is increased in clinical and experimental diabetic nephropathy, but the role of PGs in the pathogenesis and progression of diabetic nephropathy has remained unclear. It is here shown that an orally active antagonist selective for the PGE receptor EP1 subtype potently prevents the progression of nephropathy in streptozotocin-induced diabetic rats. The effects are shown by ameliorated renal and glomerular hypertrophy, decreased mesangial expansion, inhibited transcriptional activation of transforming growth factor-␤ (TGF-␤) and fibronectin, and complete suppression of proteinuria. In vitro, this agent completely inhibits TGF-␤ and fibronectin upregulation in mesangial cells cultured under high-glucose conditions. These data indicate that the PGE2-EP1 system plays a crucial role in the development of diabetic renal injury in rats. It is further shown that both the EP1 antagonist and aspirin, a nonselective PG synthase inhibitor, markedly attenuate mesangial expansion, whereas only the EP1 antagonist inhibits glomerular hypertrophy and proteinuria, which suggests that these changes are caused by different mechanisms. This study reveals a potential usefulness of selective EP1 blockade as a novel therapeutic strategy for diabetic nephropathy and also brings a new insight into our understanding of this disease.

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Section: Induction Of Diabetes and Drug Treatmentmentioning

confidence: 88%

Section: Induction Of Diabetes and Drug Treatmentmentioning

confidence: 94%

Section: Induction Of Diabetes and Drug Treatmentmentioning

confidence: 99%

Section: Induction Of Diabetes and Drug Treatmentmentioning

confidence: 99%

See 2 more Smart Citations

Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

Makino¹,

Tanaka²,

Mukoyama³

et al. 2002

Journal of the American Society of Nephrology

Self Cite

107

100

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“…In this context, it has been shown that human umbilical vein endothelial cells express both EP2 and EP4 (Dormond et al, 2002), and EP3-null mice show decreased tumor growth and angiogenesis (Amano et al, 2003). Moreover, deletion of EP1 and EP4 inhibits tumor development (Watanabe et al, 1999;Mutoh et al, 2002), clearly suggesting that different EP receptors may mediate specific aspects of tumor angiogenesis. Vascular endothelial cell survival is essential for the formation as well as function of blood vessels.…”

Section: Discussionmentioning

confidence: 99%

EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

et al. 2006

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Prostaglandin E2 (PGE 2 ), a major cyclooxygenase (COX) metabolite, plays important roles in tumor biology. We studied the role of EP2, a receptor for PGE 2 , in tumor angiogenesis using EP2 knockout mice. We found that deletion of the EP2 receptor impaired tumor angiogenesis and this finding was confirmed by an in vivo corneal angiogenesis model and an ex vivo aortic ring assay. To further characterize the cellular mechanisms of the EP2 receptor in angiogenesis, we isolated primary pulmonary endothelial cells (ECs) from wild-type (wt) and EP2 À/À mice and observed that EP2 À/À ECs exhibited defects in vascular branch formation when compared to wt ECs. In addition, EP2 À/À ECs showed impaired cell motility on collagen-coated surface and they responded poorly to PGE 2 -induced cell migration compared to control cells. However, no difference in cell proliferation was observed between the EP2 À/À and wt Ecs. In addition, EP2 À/À ECs were more susceptible to apoptosis than wt cells under growth factor depletion conditions. Collectively, our data demonstrate that EP2 signaling in endothelium directly regulates tumor angiogenesis by contributing to cell survival and endothelial cell motility. Moreover, our finding suggests that EP2 is a major receptor in PGE 2 -mediated cell motility in ECs.

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Agents Acting on Prostanoid and Thromboxane Receptors

Hall

Peace

Swarbrick

2010

Burger's Medicinal Chemistry and Drug Discovery

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Inhibitory effect of a prostaglandin E receptor subtype EP1 selective antagonist, ONO-8713, on development of azoxymethane-induced aberrant crypt foci in mice

Cited by 114 publications

References 14 publications

Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

Agents Acting on Prostanoid and Thromboxane Receptors

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