Chemopreventive effects of ONO-8711, a selective prostaglandin E receptor EP1 antagonist, on breast cancer development

Kawamori, Toshihiko; Uchiya, Naoaki; Nakatsugi, Seiichi; Watanabe, Kouji; Ohuchida, Shuichi; Yamamoto, Hiroshi; Maruyama, Takayuki; Kondo, Kazuaki; Sügimura, Takashi; Wakabayashi, Keiji

doi:10.1093/carcin/22.12.2001

Cited by 81 publications

(64 citation statements)

References 22 publications

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“…To specifically determine whether the EP 1 receptor is functionally active in HCC cells, we used a selective EP 1 receptor agonist and antagonist to analyze their effects on cell viability and migration. Previous studies showed that the EP 1 receptor antagonist AH6809 inhibited anchorage-independent cell growth and reduced the viability of HCC cells [24] ; however, ONO-8711 significantly inhibited breast cancer and HCC development, presumably via induction of apoptosis [1,25] . Our data showed that the selective EP 1 receptor agonist ONO-DI-004 dramatically increased cell viability and migration in HCC cells in a dose-dependent manner and that the EP 1 receptor antagonist ONO-8711 exerted an inhibitory effect.…”

Section: Discussionmentioning

confidence: 97%

Prostanoid EP1 receptor as the target of (−)-epigallocatechin-3-gallate in suppressing hepatocellular carcinoma cells in vitro

et al. 2012

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Aim: To investigate the effects of (-)-epigallocatechin-3-gallate (EGCG), an active compound in green tea, on prostaglandin E 2 (PGE 2 )-induced proliferation and migration, and the expression of prostanoid EP 1 receptors in hepatocellular carcinoma (HCC) cells. Methods: HCC cell line HepG2, human hepatoma cell lines MHCC-97L, MHCC-97H and human hepatocyte cell line L02 were used. Cell viability was analyzed using MTT assay. PGE 2 production was determined with immunoassay. Wound healing assay and transwell filter assay were employed to assess the extent of HCC cell migration. The expression of EP 1 receptor and Gq protein were examined using Western blot assay. Results: PGE 2 (4-40000 nmol/L) or the EP 1 receptor agonist ONO-DI-004 (400-4000 nmol/L) increased the viability and migration of HepG2 cells in concentration-dependent manners. EGCG (100 μg/mL) significantly inhibited the viability and migration of HepG2 cells induced by PGE 2 or ONO-DI-004. HepG2 cells secreted an abundant amount of PGE 2 into the medium, and EGCG (100 μg/mL) significantly inhibited the PGE 2 production and EP 1 receptor expression in HepG2 cells. EGCG (100 μg/mL) also inhibited the viability of MHCC-97L cells, but not that of MHCC-97H cells. Both EGCG (100 μg/mL) and EP 1 receptor antagonist ONO-8711 inhibited PGE 2 4 μmol/L and ONO-DI-004 400 nmol/L-induced growth and migration of HepG2 cells. Both EGCG (100 μg/mL) and ONO-8711 210 nmol/L inhibited PGE 2 -and ONO-DI-004-induced EP 1 expression. EGCG and ONO-8711 had synergistic effects in inhibiting EP 1 receptor expression. PGE 2 , ONO-DI-004, ONO-8711, and EGCG had no effects on Gq expression in HepG2 cells, respectively. Conclusion: These findings suggest that the anti-HCC effects of EGCG might be mediated, at least partially, through the suppressing EP 1 receptor expression and PGE 2 production.

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Section: Discussionmentioning

confidence: 97%

Prostanoid EP1 receptor as the target of (−)-epigallocatechin-3-gallate in suppressing hepatocellular carcinoma cells in vitro

et al. 2012

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“…PGE 2 elicits cellular responses via interaction with four cell surface receptors, EP [1][2][3][4] . Several studies suggest that the role of specific EP receptors varies in different tumor types (37)(38)(39).…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Are Overexpressed in Squamous Cell Carcinoma of the Penis

Golijanin

Tan

Kazior

et al. 2004

Clinical Cancer Research

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Purpose: Prostaglandin E 2 (PGE 2 ) promotes malignant growth. Cyclooxygenase (COX) catalyzes the synthesis of PGH 2 , which is converted, in turn, by microsomal prostaglandin E synthase (mPGES-1) to PGE 2 . One strategy for inhibiting carcinogenesis is to prevent PGE 2 production in premalignant and malignant tissues. It is important, therefore, to determine whether enzymes involved in PGE 2 biosynthesis are deregulated in neoplasia. The main purpose of this study was to determine whether amounts of COX-2 or mPGES-1 were increased in intraepithelial neoplasia or squamous cell carcinoma (SCC) of the penis. Because human papillomavirus (HPV) has been linked to the development of penile SCC, a secondary objective was to determine whether COX-2 was overexpressed in SCC arising in an HPV16 transgenic mouse.Experimental Design: Immunohistochemistry and immunoblotting were used to evaluate the expression of COX-2 and mPGES-1 in benign and malignant lesions including metastases to lymph nodes. Amounts of intratumoral PGE 2 were quantified by enzyme immunoassay. Reverse transcription-PCR was used to determine the expression of each of the four known receptors (EP 1-4 ) for PGE 2.Results: Immunohistochemistry demonstrated increased expression of COX-2 and mPGES-1 in dysplasia, carcinoma in situ, invasive SCC, and metastases to lymph nodes. Immunoblot analysis confirmed that COX-2 and mPGES-1 were consistently overexpressed in SCC. PGE 2 and all four of the PGE 2 receptor subtypes were detected in each of the tumor samples.Elevated levels of COX-2 were also detected in SCC arising in an HPV16 transgenic mouse.Conclusions: Increased amounts of COX-2 and mPGES-1 were detected in penile intraepithelial neoplasia and carcinoma. These findings provide the basis for evaluating whether inhibiting COX-2 will be useful in the prevention or treatment of penile SCC.

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“…15 Recent data suggest that antagonists (ONO-8711), which specifically block EP 1 receptor, may also exhibit chemopreventive activity in several animal models of epithelial malignancy including breast cancer. 16,17 A study by Zhao et al 18 has also shown that the EP 1 and EP 2 receptors play an important role in the regulation of aromatase, which synthesises oestrogens locally in the breast.…”

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confidence: 99%

“…16 EP 1 expression in human breast has not been studied before. We studied the expression of human EP 1 receptors by immunohistochemistry in malignant breast lesions along with COX-2, oestrogen receptor (ER), progesterone receptor (PR) and HER-2/neu to correlate the pattern of expression with known prognostic factors in breast cancer.…”

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confidence: 99%

Prostanoid receptor EP1 expression in breast cancer

et al. 2008

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Cyclooxygenase enzymes play an important role in carcinogenesis, and increased expression of cyclooxygenase enzymes has been reported in cancers arising at a number of different sites. Most, if not all of these actions are thought to be mediated by prostaglandin E2 (PGE2). The actions of PGE2 are mediated via four main prostanoid receptors, designated EP1, EP2, EP3 and EP4, based on their different pharmacological properties and secondary messenger pathways. Recently, expression of EP1 has been reported in rat mammary gland and the inhibition of this receptor has been documented to have chemopreventive effect in this animal model. EP1 has also been shown to decrease the incidence of colon cancer in mouse models. In this study, we analysed the expression of EP1 in normal and malignant breast tissues. Expression of EP1 was analysed in breast (benign and cancer) cell lines by reverse-transcriptase polymerase chain reaction and by western blot analyses. Expression was also analysed by immunohistochemistry in normal breast tissues and in 89 cases of breast cancer. Semiquantitative analysis of the staining was performed. The data were compared with and correlated with other prognostic factors like tumour size, tumour grade, lymph node status, oestrogen receptor, progesterone receptor (PR), HER2/neu and cyclooxygenase-2. EP1 expression was demonstrated in human breast cancer by immunohistochemistry. Expression of EP1 was seen both in the cytoplasm and/or in the nuclear membrane in majority of cases. Nuclear EP1 expression correlated with PR (P ¼ 0.032) and inversely with node positivity (P ¼ 0.025). However, EP1 expression did not correlate with expression of cyclooxygenase-2 (P ¼ 0.059). Expression of EP1 is frequently seen in human breast cancers. Nuclear expression of EP1 correlates with good prognosis markers like node negative status and PR expression. Keywords: breast cancer; EP1 receptor; cyclooxygenase; PGE2; prostanoid receptor; immunohistochemistry Breast cancer is one of the most common malignancies in developed countries including USA, and the second leading cause of cancer-related deaths in women. 1 As the incidence of breast cancer is increasing, several attempts at testing various preventive agents have been made (reviewed by Arun and Hortobagyi 2 ). Nonsteroidal anti-inflammatory drugs (NSAIDs), which act through inhibition of cyclooxygenase enzyme (COX), are one such class of drugs that have been studied for their possible role in breast cancer prevention. Epidemiological studies investigating the relationship between NSAID use and breast cancer have reported conflicting results; some studies 3-5 show 30-40% reduction in breast cancer incidence with NSAID use, whereas others failed to confirm this relationship. 6,7 NSAIDs work by inhibiting both constitutive and inducible cyclooxygenase enzymes (COX-1 and COX-2, respectively), both of which have been postulated to play a role in carcinogenesis. Elevated cyclooxygenase-2 (COX-2) expression is a marker of poor prognosis in human breast cancer and correla...

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Chemopreventive effects of ONO-8711, a selective prostaglandin E receptor EP1 antagonist, on breast cancer development

Cited by 81 publications

References 22 publications

Prostanoid EP1 receptor as the target of (−)-epigallocatechin-3-gallate in suppressing hepatocellular carcinoma cells in vitro

Prostanoid EP1 receptor as the target of (−)-epigallocatechin-3-gallate in suppressing hepatocellular carcinoma cells in vitro

Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Are Overexpressed in Squamous Cell Carcinoma of the Penis

Prostanoid receptor EP1 expression in breast cancer

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