The Experts below are selected from a list of 279 Experts worldwide ranked by ideXlab platform
Graham P. Pidgeon - One of the best experts on this subject based on the ideXlab platform.
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examination of Thromboxane Synthase as a prognostic factor and therapeutic target in non small cell lung cancer
Molecular Cancer, 2011Co-Authors: Mary Clare Cathcart, Kenneth J Obyrne, Kathy Gately, Robert Cummins, Graham P. PidgeonAbstract:Thromboxane Synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane Synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
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Examination of Thromboxane Synthase as a prognostic factor and therapeutic target in non-small cell lung cancer
Molecular Cancer, 2011Co-Authors: Mary Clare Cathcart, Kathy Gately, Robert Cummins, Kenneth J. O'byrne, Graham P. PidgeonAbstract:Background: Thromboxane Synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. Methods: TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results: TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion: TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane Synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
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examination of Thromboxane Synthase as a prognostic factor and therapeutic target in non small cell lung cancer
Faculty of Health; Institute of Health and Biomedical Innovation, 2011Co-Authors: Mary Clare Cathcart, Kenneth J Obyrne, Kathy Gately, Robert Cummins, Graham P. PidgeonAbstract:Background: Thromboxane Synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. Methods: TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB 2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results: TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB 2levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion: TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane Synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC. © 2011 Cathcart et al; licensee BioMed Central Ltd.
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the role of prostacyclin Synthase and Thromboxane Synthase signaling in the development and progression of cancer
Biochimica et Biophysica Acta, 2010Co-Authors: Mary Clare Cathcart, John V Reynolds, Kenneth J Obyrne, Graham P. PidgeonAbstract:Prostacyclin Synthase and Thromboxane Synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective Synthases differ considerably with respect to the pathways described. While prostacyclin Synthase is generally believed to be anti-tumor, a pro-carcinogenic role for Thromboxane Synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI2/TXA2 ratio is of particular interest in-vivo, with the corresponding Synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of Thromboxane Synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin Synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin Synthase and Thromboxane Synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer.
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the role of prostacyclin Synthase and Thromboxane Synthase signaling in the development and progression of cancer
Faculty of Health; Institute of Health and Biomedical Innovation, 2010Co-Authors: Mary Clare Cathcart, John V Reynolds, Kenneth J Obyrne, Graham P. PidgeonAbstract:Prostacyclin Synthase and Thromboxane Synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective Synthases differ considerably with respect to the pathways described. While prostacyclin Synthase is generally believed to be anti-tumor, a pro-carcinogenic role for Thromboxane Synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI2/TXA2 ratio is of particular interest in-vivo, with the corresponding Synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of Thromboxane Synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin Synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin Synthase and Thromboxane Synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer. © 2010 Elsevier B.V. All rights reserved.
Mary Clare Cathcart - One of the best experts on this subject based on the ideXlab platform.
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examination of Thromboxane Synthase as a prognostic factor and therapeutic target in non small cell lung cancer
Molecular Cancer, 2011Co-Authors: Mary Clare Cathcart, Kenneth J Obyrne, Kathy Gately, Robert Cummins, Graham P. PidgeonAbstract:Thromboxane Synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane Synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
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Examination of Thromboxane Synthase as a prognostic factor and therapeutic target in non-small cell lung cancer
Molecular Cancer, 2011Co-Authors: Mary Clare Cathcart, Kathy Gately, Robert Cummins, Kenneth J. O'byrne, Graham P. PidgeonAbstract:Background: Thromboxane Synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. Methods: TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results: TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion: TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane Synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
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examination of Thromboxane Synthase as a prognostic factor and therapeutic target in non small cell lung cancer
Faculty of Health; Institute of Health and Biomedical Innovation, 2011Co-Authors: Mary Clare Cathcart, Kenneth J Obyrne, Kathy Gately, Robert Cummins, Graham P. PidgeonAbstract:Background: Thromboxane Synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. Methods: TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB 2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results: TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB 2levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion: TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane Synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC. © 2011 Cathcart et al; licensee BioMed Central Ltd.
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the role of prostacyclin Synthase and Thromboxane Synthase signaling in the development and progression of cancer
Biochimica et Biophysica Acta, 2010Co-Authors: Mary Clare Cathcart, John V Reynolds, Kenneth J Obyrne, Graham P. PidgeonAbstract:Prostacyclin Synthase and Thromboxane Synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective Synthases differ considerably with respect to the pathways described. While prostacyclin Synthase is generally believed to be anti-tumor, a pro-carcinogenic role for Thromboxane Synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI2/TXA2 ratio is of particular interest in-vivo, with the corresponding Synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of Thromboxane Synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin Synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin Synthase and Thromboxane Synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer.
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the role of prostacyclin Synthase and Thromboxane Synthase signaling in the development and progression of cancer
Faculty of Health; Institute of Health and Biomedical Innovation, 2010Co-Authors: Mary Clare Cathcart, John V Reynolds, Kenneth J Obyrne, Graham P. PidgeonAbstract:Prostacyclin Synthase and Thromboxane Synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective Synthases differ considerably with respect to the pathways described. While prostacyclin Synthase is generally believed to be anti-tumor, a pro-carcinogenic role for Thromboxane Synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI2/TXA2 ratio is of particular interest in-vivo, with the corresponding Synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of Thromboxane Synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin Synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin Synthase and Thromboxane Synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer. © 2010 Elsevier B.V. All rights reserved.
Shripad S. Bhagwat - One of the best experts on this subject based on the ideXlab platform.
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Thromboxane receptor antagonism combined with Thromboxane Synthase inhibition. 6. 4-substituted 3-pyridinylalkanoic acids.
Bioorganic & Medicinal Chemistry Letters, 1992Co-Authors: Shripad S. Bhagwat, D.s. Cohen, R. Dotson, J. Mathis, Clay Boswell, Candido Gude, N. Contardo, Suraj Shivappa ShettyAbstract:Abstract (3-Pyridinyl)alkanoic acids substituted at the 4-position with an (arylsulfonamido)alkyl group were synthesized and found to behave as platelet Thromboxane receptor antagonists (TxRAs) and Thromboxane Synthase inhibitors (TxSIs). The compounds behaved as agonists at the vascular receptor for Thromboxane A2.
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Thromboxane receptor antagonism combined with Thromboxane Synthase inhibition. 7. pyridinylalkyl-substituted arylsulfonylamino arylalkanoic acids.
Bioorganic & Medicinal Chemistry Letters, 1992Co-Authors: Shripad S. Bhagwat, D.s. Cohen, R. Dotson, Candido Gude, D.m. Roland, Alan Joseph Main, K. Grim, Robert Goldstein, J. MathisAbstract:Abstract Arylsulfonylamino arylalkanoic acids substituted with a pyridinylalkyl group on the arylalkanoic acid portion of the molecule were synthesized and found to behave as Thromboxane receptor antagonists (TxRAs) and Thromboxane Synthase inhibitors (TxSIs). One of these compounds (11), with a 1,3,5-trisubstituted central aromatic ring was demonstrated to have good functional bioavailability and efficacy as a platelet inhibitor in guinea pigs.
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Thromboxane receptor antagonism combined with Thromboxane Synthase inhibition. 3. Pyridinylalkyl-substituted 8-[(arylsulfonyl)amino]octanoic acids.
Journal of Medicinal Chemistry, 1992Co-Authors: Alan Joseph Main, Shripad S. Bhagwat, Clay Boswell, Candido Gude, Robert Goldstein, Patricia Furness, D. M. Cohen, Marissa LouzanAbstract:: A series of 8-[(arylsulfonyl)amino]octanoic acids substituted with a pyridinylalkyl group along the chain were synthesized and tested in vitro for their ability to both antagonize the binding of Thromboxane A2 to its receptors and to inhibit the Thromboxane Synthase enzyme. This series of compounds were found to inhibit the U 46619-induced aggregation of human platelets and the U 46619-induced contraction of dog saphenous vein. The compounds also inhibited TxA2 biosynthesis in a human microsomal platelet preparation. The relative position of the pyridinylalkyl and arylsulfonamide groups had significant effects on the Thromboxane receptor antagonist (TxRA) activity and Thromboxane Synthase inhibitor (TxSI) activity. Compounds with the pyridine ring at the 7- or 8-position of the octanoic acid side chain were weakly active as TxSI but behaved as potent TxRA at the platelet receptor for TxA2. However, these compounds were agonists at the vascular receptor. Substitution of the pyridinylalkyl group at the 2- or 3-position resulted in compounds with potent TxSI activity and weak TxRA activity. The activity profile of the compounds with the pyridinylalkyl substitution at the 4-, 5-, or 6-position was very desirable. Compound 22 with a pyridinylpropyl substituent at the 4-position was found to display extremely potent TxRA and TxSI properties.
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Thromboxane receptor antagonism combined with Thromboxane Synthase inhibition 1 3 pyridinylbicycloheptyl alkanoic acids
Journal of Medicinal Chemistry, 1991Co-Authors: Shripad S. Bhagwat, Candido Gude, David S Cohen, Patricia Furness, Frank H ClarkeAbstract:The design, synthesis, and in vitro pharmacology of a new class of compounds exerting both Thromboxane receptor antagonist and Thromboxane Synthase inhibitory activities is described. [(3-Pyridinyl)bicycloheptyl]alkanoic acid 9 and its analogues, designed with the help of molecular modeling, were synthesized and found to be inhibitors of Thromboxane A 2 (TxA 2 ) biosynthesis in a human platelet microsomal preparation. The compounds were also found to antagonize both platelet and vascular TxA 2 receptors. The compounds inhibited the U 46619 induced aggregation of human washed platelets and platelet-rich plasma and the U 46619 induced contraction of the dog saphenous vein
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Thromboxane receptor antagonism combined with Thromboxane Synthase inhibition. 1. (+/-)-(3-pyridinylbicycloheptyl)alkanoic acids.
Journal of Medicinal Chemistry, 1991Co-Authors: Shripad S. Bhagwat, Candido Gude, David S Cohen, Patricia Furness, Frank H ClarkeAbstract:The design, synthesis, and in vitro pharmacology of a new class of compounds exerting both Thromboxane receptor antagonist and Thromboxane Synthase inhibitory activities is described. [(3-Pyridinyl)bicycloheptyl]alkanoic acid 9 and its analogues, designed with the help of molecular modeling, were synthesized and found to be inhibitors of Thromboxane A 2 (TxA 2 ) biosynthesis in a human platelet microsomal preparation. The compounds were also found to antagonize both platelet and vascular TxA 2 receptors. The compounds inhibited the U 46619 induced aggregation of human washed platelets and platelet-rich plasma and the U 46619 induced contraction of the dog saphenous vein
Alf Giese - One of the best experts on this subject based on the ideXlab platform.
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inhibition of Thromboxane Synthase activity improves glioblastoma response to alkylation chemotherapy
Translational Oncology, 2010Co-Authors: Nils Ole Schmidt, Manfred Westphal, Alf Giese, Theresa G Cargioli, Peter Mcl Black, Rona S CarrollAbstract:Thromboxane Synthase (TXSA), an enzyme of the arachidonic acid metabolism, is upregulated in human glial tumors and is involved in glioma progression. Here, we analyzed the in vitro and in vivo effects of pharmacological inhibition of TXSA activity on human glioblastoma cells. Furegrelate, a specific inhibitor of TXSA, significantly inhibited tumor growth in an orthotopic glioblastoma model by inducing proapoptotic, antiproliferative, and antiangiogenic effects. Inhibition of TXSA induced a proapoptotic disposition of glioma cells and increased the sensitivity to the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea, significantly prolonging the survival time of intracerebral glioma-bearing mice. Our data demonstrate that the targeted inhibition of TXSA activity improves the efficiency of conventional alkylation chemotherapy in vivo. Our study supports the role of TXSA activity for the progression of malignant glioma and the potential utility of its therapeutic modulation for glioma treatment.
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Inhibition of invasion-associated Thromboxane Synthase sensitizes experimental gliomas to γ-radiation
Journal of Neuro-Oncology, 2009Co-Authors: Anne Katrin Schauff, Jan Leppert, Roger Nadrowitz, Robin Wuestenberg, Mark Alexander Brockmann, Alf GieseAbstract:The invasion- and apoptosis-associated Thromboxane Synthase gene encoding an enzyme of the arachidonic acid pathway has been implicated in glioma progression. Furegrelate, a specific inhibitor of Thromboxane Synthase, blocks cell motility, induces apoptosis and increases sensitivity to drug induced apoptosis in human glioma cells in vitro. The impact of furegrelate on the sensitivity of human glioma cells to γ-irradiation was analyzed using colony formation assay in vitro and an orthotopic mouse model in vivo. Pre-treatment of glioma cells with furegrelate increases radiation sensitivity of cultured glioma cells. Treatment of experimental gliomas with suboptimal doses of radiation and furegrelate results in a significant decrease in tumor volumes compared to untreated controls. Thus, the specific Thromboxane Synthase inhibitor furegrelate increases death response induced by γ-radiation in glioma cells in vitro and sensitizes experimental gliomas to radiation treatment in vivo .
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Thromboxane Synthase inhibitors induce apoptosis in migration arrested glioma cells
Neurosurgery, 2002Co-Authors: Kimio Yoshizato, Svenja Zapf, Manfred Westphal, Michael E Berens, Alf GieseAbstract:OBJECTIVE: Because of the wide dissemination of malignant glioma cells by the time that malignant glioma is diagnosed, anti-invasive strategies that are designed to limit their further spread may be of little value unless mechanisms of the invasive cascade can be used to render invasive cells susceptible to cytoreductive treatments. We recently determined that elevated Thromboxane Synthase gene expression and enzymatic activity are associated with a highly migratory phenotype of glioma cells in vitro and that specific inhibitors of this enzyme block cell migration. Interference with this inherent phenotype of malignant gliomas also affects glioma cell proliferation and apoptosis. METHODS: To study the effect of Thromboxane Synthase inhibitors on motility, metabolic activity, and cell death, we used five human glioma cell lines, four glioblastoma-derived, low-passage cell cultures, normal human astrocytes, and fibroblasts. Motility was measured in a monolayer migration assay. Caspase activation as an early event in apoptotic cell death was assessed using a caspase 3 cleavage assay. Intracellular deoxyribonucleic acid (DNA) fragmentation was detected by enzyme-linked immunosorbent assay quantification of histone-complexed DNA. Subsequent cell death was scored by trypan blue exclusion. RESULTS: In this study, we demonstrate that the treatment of human glioma cells with the specific Thromboxane Synthase inhibitor furegrelate leads first to caspase activation (detectable 6 h after treatment), then to DNA fragmentation (24-48 h after treatment) and subsequent cell death. Caspase inhibitors abrogate this effect. Furthermore, the inhibition of Thromboxane Synthase by furegrelate increases cells' susceptibility to the induction of DNA fragmentation by camptothecin, etoposide, N,N'-bis(2-chloroethyl)-N-nitrosourea, and anti-CD95 antibodies. No induction of apoptosis was observed in normal astrocytes and fibroblasts. CONCLUSION: These data indicate that Thromboxane Synthase may represent a vortex of divergent signaling cascades that regulate motility and apoptosis in glioma cells. This paradigm may offer a novel perspective in the treatment of patients with malignant gliomas.
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cyclo oxygenase inhibitors and Thromboxane Synthase inhibitors differentially regulate migration arrest growth inhibition and apoptosis in human glioma cells
Acta Neurochirurgica, 2002Co-Authors: F Kurzel, Svenja Zapf, Manfred Westphal, Ch Hagel, Hildegard Meissner, Alf GieseAbstract:: We have previously identified Thromboxane Synthase as an important regulator of glioma cell migration. Inhibitors of this enzyme abrogate cell motility and induce apoptosis. However, the formation rate of Thromboxanes is indirectly dependent on the activity of cyclo-oxygenase, which represents the rate-limiting step in the synthesis of prostaglandins and Thromboxanes. In this study we have analyzed the expression of COX-1 and COX-2 in glioma cell lines and biopsies of glial tumors. In normal glia no expression of both COX isoforms was present, however, reactive astrocytes and glial tumors of all grades demonstrated expression of both COX-1 and COX-2. In contrast to inhibitors of Thromboxane Synthase, selective and non-selective cyclo-oxygenase inhibitors did not block cell motility. Specific COX-2 inhibitors resulted in growth inhibition and induction of intracellular DNA fragmentation indicative of apoptotic cell death. Treatment of glioma cells with Thromboxane Synthase inhibitors had a synergistic effect on induction of apoptosis by camptothecin, whereas COX inhibitors had not. Furthermore, combined treatment using COX-2 inhibitors and specific Thromboxane Synthase inhibitors did not show a synergistic increase of apoptosis. These data indicate that COX inhibitors and Thromboxane Synthase inhibitors influence apoptosis in glioma cells through different pathways. We hypothesize that, in contrast to the COX-2 inhibitors, Thromboxane Synthase inhibitors block the invasive phenotype of glioma cells and therefore increase the pro-apoptotic disposition of the cells and increase the susceptibility to induced apoptosis. This effect may be independent of prostaglandin synthesis controlled by cyclo-oxygenases.
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altered gene expression in human astrocytoma cells selected for migration i Thromboxane Synthase
Journal of Neuropathology and Experimental Neurology, 1998Co-Authors: Wendy S Mcdonough, Alf Giese, Nhan Tran, Sylvia A Norman, Michael E BerensAbstract:Human glioma cells from a long-term cell line were selected for their ability to migrate on a glioma-derived extracellular matrix. When tested over 28 serial passages, the migration-selected strain showed a genetically stable, enhanced migration rate compared with the parental cells. Proliferation studies demonstrated that the growth rate of migration-selected cells was slightly arrested. Both the selected strain and the parental culture showed anchorage-independent growth in soft agarose and were tumorigenic in athymic mice. Using molecular genetic strategies' display to isolate genes expressed differentially between the 2 populations, a 300-bp sequence homologous to Thromboxane Synthase was upregulated in the migration-selected cells relative to the parental cells. Expression levels of Thromboxane Synthase were highly elevated in the migration-selected cells when assessed by RNAse-protection assay and by flow cytometry. Two specific Thromboxane Synthase inhibitors, Dazmegrel and Furegrelate, reduced the migration rate of the migration-selected cells to a rate equal to or less than the rate exhibited by the parental cells, respectively. The inhibitors effect on the parental cells was inconsequential. These results suggest that aberrations in the regulation of Thromboxane Synthase expression or activity may influence the motility of human glioma cells.
Kenneth J Obyrne - One of the best experts on this subject based on the ideXlab platform.
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examination of Thromboxane Synthase as a prognostic factor and therapeutic target in non small cell lung cancer
Molecular Cancer, 2011Co-Authors: Mary Clare Cathcart, Kenneth J Obyrne, Kathy Gately, Robert Cummins, Graham P. PidgeonAbstract:Thromboxane Synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane Synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
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examination of Thromboxane Synthase as a prognostic factor and therapeutic target in non small cell lung cancer
Faculty of Health; Institute of Health and Biomedical Innovation, 2011Co-Authors: Mary Clare Cathcart, Kenneth J Obyrne, Kathy Gately, Robert Cummins, Graham P. PidgeonAbstract:Background: Thromboxane Synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. Methods: TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB 2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results: TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB 2levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion: TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane Synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC. © 2011 Cathcart et al; licensee BioMed Central Ltd.
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the role of prostacyclin Synthase and Thromboxane Synthase signaling in the development and progression of cancer
Biochimica et Biophysica Acta, 2010Co-Authors: Mary Clare Cathcart, John V Reynolds, Kenneth J Obyrne, Graham P. PidgeonAbstract:Prostacyclin Synthase and Thromboxane Synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective Synthases differ considerably with respect to the pathways described. While prostacyclin Synthase is generally believed to be anti-tumor, a pro-carcinogenic role for Thromboxane Synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI2/TXA2 ratio is of particular interest in-vivo, with the corresponding Synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of Thromboxane Synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin Synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin Synthase and Thromboxane Synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer.
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the role of prostacyclin Synthase and Thromboxane Synthase signaling in the development and progression of cancer
Faculty of Health; Institute of Health and Biomedical Innovation, 2010Co-Authors: Mary Clare Cathcart, John V Reynolds, Kenneth J Obyrne, Graham P. PidgeonAbstract:Prostacyclin Synthase and Thromboxane Synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective Synthases differ considerably with respect to the pathways described. While prostacyclin Synthase is generally believed to be anti-tumor, a pro-carcinogenic role for Thromboxane Synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI2/TXA2 ratio is of particular interest in-vivo, with the corresponding Synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of Thromboxane Synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin Synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin Synthase and Thromboxane Synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer. © 2010 Elsevier B.V. All rights reserved.