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Christoph J. Auernhammer - One of the best experts on this subject based on the ideXlab platform.
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The novel somatostatin receptor 2/dopamine type 2 receptor chimeric compound BIM-23A758 decreases the viability of human GOT1 midgut Carcinoid cells.
Neuroendocrinology, 2013Co-Authors: Kathrin Zitzmann, Burkhard Göke, Sandra Andersen, George Vlotides, Gerald Spöttl, Shengwen Zhang, Rakesh Datta, Michael D. Culler, Christoph J. AuernhammerAbstract:The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system coexpress somatostatin receptors (SSTRs) and dopamine type 2 receptors (D2R), thus providing a rationale for the use of novel SSTR2/D2R chimeric compounds in NET disease. Here we investigate the antitumor potential of the SSTR2/D2R chimeric compounds BIM-23A760 and BIM-23A758 in comparison to the selective SSTR2 agonist BIM-23023 and the selective D2R agonist BIM-53097 on human NET cell lines of heterogeneous origin. While having only minor effects on human pancreatic and Bronchus Carcinoid cells (BON1 and NCI-H727), BIM-23A758 induced significant antitumor effects in human midgut Carcinoid cells (GOT1). These effects involved apoptosis induction as well as inhibition of mitogen-activated protein kinase and Akt signaling. Consistent with their antitumor response to BIM-23A758, GOT1 cells showed relatively high expression levels of SSTR2 and D2R mRNA. In particular, GOT1 cells highly express the short transcript variant of D2R. In contrast to BIM-23A758, the SSTR2/D2R chimeric compound BIM-23A760 as well as the individual SSTR2 and D2R agonistic compounds BIM-23023 and BIM-53097 induced no or only minor antitumor responses in the examined NET cell lines. Taken together, our findings suggest that the novel SSTR2/D2R chimeric compound BIM-23A758 might be a promising substance for the treatment of NETs highly expressing SSTR2 and D2R. In particular, a sufficient expression of the short transcript variant of DR2 might play a pivotal role for effective treatment.
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The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells
Endocrine-related cancer, 2011Co-Authors: Kathrin Zitzmann, Enrico N. De Toni, Janina Von Rüden, Stephan Brand, Burkhard Göke, Rüdiger P. Laubender, Christoph J. AuernhammerAbstract:The tumour-selective death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for the treatment of human cancer. However, many tumours have evolved mechanisms to resist TRAIL-induced apoptosis. A number of studies have demonstrated that aberrant PI(3)K-Akt-mTOR survival signalling may confer TRAIL resistance by altering the balance between pro- and anti-apoptotic proteins. Here, we show that neuroendocrine tumour (NET) cell lines of heterogeneous origin exhibit a range of TRAIL sensitivities and that TRAIL sensitivity correlates with the expression of FLIP(S), caspase-8, and Bcl-2. Neither single mTOR inhibition by everolimus nor dual mTOR/PI(3)K inhibition by NVP-BEZ235 was able to enhance TRAIL susceptibility in any of the tested cell lines. In contrast, dual PI(3)K-Akt-mTOR and Raf-MEK-Erk pathway inhibition by the IGF-1R inhibitor NVP-AEW541 effectively restored TRAIL sensitivity in NCI-H727 Bronchus Carcinoid cells. Furthermore, blocking Raf-MEK-Erk signalling by the novel Raf inhibitor Raf265 significantly enhanced TRAIL sensitivity in NCI-H727 and CM insulinoma cells. While having no effect on FLIP(S) or caspase-8 expression, Raf265 strongly decreased Bcl-2 levels in those cell lines susceptible to its TRAIL-sensitizing action. Taken together, our findings suggest that combinations of Raf-MEK-Erk pathway inhibitors and TRAIL might offer a novel therapeutic strategy in NET disease.
Kathrin Zitzmann - One of the best experts on this subject based on the ideXlab platform.
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The novel somatostatin receptor 2/dopamine type 2 receptor chimeric compound BIM-23A758 decreases the viability of human GOT1 midgut Carcinoid cells.
Neuroendocrinology, 2013Co-Authors: Kathrin Zitzmann, Burkhard Göke, Sandra Andersen, George Vlotides, Gerald Spöttl, Shengwen Zhang, Rakesh Datta, Michael D. Culler, Christoph J. AuernhammerAbstract:The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system coexpress somatostatin receptors (SSTRs) and dopamine type 2 receptors (D2R), thus providing a rationale for the use of novel SSTR2/D2R chimeric compounds in NET disease. Here we investigate the antitumor potential of the SSTR2/D2R chimeric compounds BIM-23A760 and BIM-23A758 in comparison to the selective SSTR2 agonist BIM-23023 and the selective D2R agonist BIM-53097 on human NET cell lines of heterogeneous origin. While having only minor effects on human pancreatic and Bronchus Carcinoid cells (BON1 and NCI-H727), BIM-23A758 induced significant antitumor effects in human midgut Carcinoid cells (GOT1). These effects involved apoptosis induction as well as inhibition of mitogen-activated protein kinase and Akt signaling. Consistent with their antitumor response to BIM-23A758, GOT1 cells showed relatively high expression levels of SSTR2 and D2R mRNA. In particular, GOT1 cells highly express the short transcript variant of D2R. In contrast to BIM-23A758, the SSTR2/D2R chimeric compound BIM-23A760 as well as the individual SSTR2 and D2R agonistic compounds BIM-23023 and BIM-53097 induced no or only minor antitumor responses in the examined NET cell lines. Taken together, our findings suggest that the novel SSTR2/D2R chimeric compound BIM-23A758 might be a promising substance for the treatment of NETs highly expressing SSTR2 and D2R. In particular, a sufficient expression of the short transcript variant of DR2 might play a pivotal role for effective treatment.
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The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells
Endocrine-related cancer, 2011Co-Authors: Kathrin Zitzmann, Enrico N. De Toni, Janina Von Rüden, Stephan Brand, Burkhard Göke, Rüdiger P. Laubender, Christoph J. AuernhammerAbstract:The tumour-selective death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for the treatment of human cancer. However, many tumours have evolved mechanisms to resist TRAIL-induced apoptosis. A number of studies have demonstrated that aberrant PI(3)K-Akt-mTOR survival signalling may confer TRAIL resistance by altering the balance between pro- and anti-apoptotic proteins. Here, we show that neuroendocrine tumour (NET) cell lines of heterogeneous origin exhibit a range of TRAIL sensitivities and that TRAIL sensitivity correlates with the expression of FLIP(S), caspase-8, and Bcl-2. Neither single mTOR inhibition by everolimus nor dual mTOR/PI(3)K inhibition by NVP-BEZ235 was able to enhance TRAIL susceptibility in any of the tested cell lines. In contrast, dual PI(3)K-Akt-mTOR and Raf-MEK-Erk pathway inhibition by the IGF-1R inhibitor NVP-AEW541 effectively restored TRAIL sensitivity in NCI-H727 Bronchus Carcinoid cells. Furthermore, blocking Raf-MEK-Erk signalling by the novel Raf inhibitor Raf265 significantly enhanced TRAIL sensitivity in NCI-H727 and CM insulinoma cells. While having no effect on FLIP(S) or caspase-8 expression, Raf265 strongly decreased Bcl-2 levels in those cell lines susceptible to its TRAIL-sensitizing action. Taken together, our findings suggest that combinations of Raf-MEK-Erk pathway inhibitors and TRAIL might offer a novel therapeutic strategy in NET disease.
Burkhard Göke - One of the best experts on this subject based on the ideXlab platform.
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The novel somatostatin receptor 2/dopamine type 2 receptor chimeric compound BIM-23A758 decreases the viability of human GOT1 midgut Carcinoid cells.
Neuroendocrinology, 2013Co-Authors: Kathrin Zitzmann, Burkhard Göke, Sandra Andersen, George Vlotides, Gerald Spöttl, Shengwen Zhang, Rakesh Datta, Michael D. Culler, Christoph J. AuernhammerAbstract:The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system coexpress somatostatin receptors (SSTRs) and dopamine type 2 receptors (D2R), thus providing a rationale for the use of novel SSTR2/D2R chimeric compounds in NET disease. Here we investigate the antitumor potential of the SSTR2/D2R chimeric compounds BIM-23A760 and BIM-23A758 in comparison to the selective SSTR2 agonist BIM-23023 and the selective D2R agonist BIM-53097 on human NET cell lines of heterogeneous origin. While having only minor effects on human pancreatic and Bronchus Carcinoid cells (BON1 and NCI-H727), BIM-23A758 induced significant antitumor effects in human midgut Carcinoid cells (GOT1). These effects involved apoptosis induction as well as inhibition of mitogen-activated protein kinase and Akt signaling. Consistent with their antitumor response to BIM-23A758, GOT1 cells showed relatively high expression levels of SSTR2 and D2R mRNA. In particular, GOT1 cells highly express the short transcript variant of D2R. In contrast to BIM-23A758, the SSTR2/D2R chimeric compound BIM-23A760 as well as the individual SSTR2 and D2R agonistic compounds BIM-23023 and BIM-53097 induced no or only minor antitumor responses in the examined NET cell lines. Taken together, our findings suggest that the novel SSTR2/D2R chimeric compound BIM-23A758 might be a promising substance for the treatment of NETs highly expressing SSTR2 and D2R. In particular, a sufficient expression of the short transcript variant of DR2 might play a pivotal role for effective treatment.
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The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells
Endocrine-related cancer, 2011Co-Authors: Kathrin Zitzmann, Enrico N. De Toni, Janina Von Rüden, Stephan Brand, Burkhard Göke, Rüdiger P. Laubender, Christoph J. AuernhammerAbstract:The tumour-selective death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for the treatment of human cancer. However, many tumours have evolved mechanisms to resist TRAIL-induced apoptosis. A number of studies have demonstrated that aberrant PI(3)K-Akt-mTOR survival signalling may confer TRAIL resistance by altering the balance between pro- and anti-apoptotic proteins. Here, we show that neuroendocrine tumour (NET) cell lines of heterogeneous origin exhibit a range of TRAIL sensitivities and that TRAIL sensitivity correlates with the expression of FLIP(S), caspase-8, and Bcl-2. Neither single mTOR inhibition by everolimus nor dual mTOR/PI(3)K inhibition by NVP-BEZ235 was able to enhance TRAIL susceptibility in any of the tested cell lines. In contrast, dual PI(3)K-Akt-mTOR and Raf-MEK-Erk pathway inhibition by the IGF-1R inhibitor NVP-AEW541 effectively restored TRAIL sensitivity in NCI-H727 Bronchus Carcinoid cells. Furthermore, blocking Raf-MEK-Erk signalling by the novel Raf inhibitor Raf265 significantly enhanced TRAIL sensitivity in NCI-H727 and CM insulinoma cells. While having no effect on FLIP(S) or caspase-8 expression, Raf265 strongly decreased Bcl-2 levels in those cell lines susceptible to its TRAIL-sensitizing action. Taken together, our findings suggest that combinations of Raf-MEK-Erk pathway inhibitors and TRAIL might offer a novel therapeutic strategy in NET disease.
Tulassay Zsolt - One of the best experts on this subject based on the ideXlab platform.
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Hatékony somatostatinanalóg-kezelés hormonálisan inaktív Carcinoid daganatos betegben: a szérum-chromogranin-A alkalmazása a klinikai követés során = Effective treatment of a hormonally inactive Carcinoid tumour with somatostatin analogues: applicati
'Akademiai Kiado Zrt.', 2027Co-Authors: Igaz Péter, Rácz Károly, Tulassay ZsoltAbstract:A Carcinoid daganatok jelentős hányada hormonálisan inaktív. E daganatok diagnózisára és követésére a klasszikusan alkalmazott biokémiai, illetőleg hormonvizsgálatok nem alkalmasak, de a neuroendokrin daganatok többségére jellemző tumormarkert, a chromogranin-A-t a hormontúltermeléssel nem járó Carcinoid daganatok is termelhetik. A hormonálisan inaktív Carcinoidokra is jellemző a somatostatin-receptorok expressziója, ami mind a képalkotó diagnózis, mind a kezelés terén nagy jelentôségű. Esetismertetés: A szerzők egy bronchialis kiindulású, többszörös májáttéteket adó, hormonálisan inaktív Carcinoid daganatban szenvedô beteg kórtörténetét ismertetik. A Bronchus Carcinoid műtéti eltávolítását követően kialakult májáttétek somatostatinreceptor-expressziójára alapozva, tartós hatású octreotidkezelést, valamint ittriumizotóppal kapcsolt somatostatin-analóg terápiát alkalmaztak. A kezelés megkezdése előtt jelentősen megnövekedett szérumchromogranin-A-szint a kezelések hatására fokozatosan csökkent. A 19 hónapos észlelés időtartama alatt a májáttétek mérete és száma nem növekedett. Következtetés: A szérum-chromogranin-A hatékonyan alkalmazható a hormonálisan inaktív Carcinoid daganatok klinikai követésére. A somatostatin-analógok nemcsak a hormontúltermeléssel járó, hanem a hormonálisan inaktív Carcinoidok esetében is gátolhatják a daganat progresszióját. Introduction: Hormonally inactive Carcinoids represent a significant proportion of all Carcinoids tumours. Classical biochemical and hormonal parameters are not suitable for the diagnosis and follow-up of these tumours. However, the tumour marker chromogranin A that is characteristic for several neuroendocrine tumours and secreted by the majority of these tumours as well, may offer a better means of diagnosis and follow-up. Somatostatin receptors are expressed by hormonally inactive Carcinoids and the presence of these receptors has important diagnostic and therapeutic consequences. Case report: The authors present the history of a patient with a hormonally inactive bronchial Carcinoid tumour. After surgical removal of the bronchial Carcinoid, liver metastases developed which were found to be somatostatin receptor positive. Somatostatin analogue treatment was introduced, followed by Yttrium-isotope labelled somatostatin analogue therapy. Serum chromogranin A was elevated before somatostatin treatment, and gradually decreased in parallel with therapy. The size of liver metastases remained unchanged during treatment. Conclusions: Chromogranin A can be efficiently applied for the clinical follow-up of hormonally inactive Carcinoid tumours. Somatostatin analogues may be effective for preventing tumour progression not only in hormone-secreting but also in hormonally inactive Carcinoid tumours
Igaz Péter - One of the best experts on this subject based on the ideXlab platform.
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Hatékony somatostatinanalóg-kezelés hormonálisan inaktív Carcinoid daganatos betegben: a szérum-chromogranin-A alkalmazása a klinikai követés során = Effective treatment of a hormonally inactive Carcinoid tumour with somatostatin analogues: applicati
'Akademiai Kiado Zrt.', 2027Co-Authors: Igaz Péter, Rácz Károly, Tulassay ZsoltAbstract:A Carcinoid daganatok jelentős hányada hormonálisan inaktív. E daganatok diagnózisára és követésére a klasszikusan alkalmazott biokémiai, illetőleg hormonvizsgálatok nem alkalmasak, de a neuroendokrin daganatok többségére jellemző tumormarkert, a chromogranin-A-t a hormontúltermeléssel nem járó Carcinoid daganatok is termelhetik. A hormonálisan inaktív Carcinoidokra is jellemző a somatostatin-receptorok expressziója, ami mind a képalkotó diagnózis, mind a kezelés terén nagy jelentôségű. Esetismertetés: A szerzők egy bronchialis kiindulású, többszörös májáttéteket adó, hormonálisan inaktív Carcinoid daganatban szenvedô beteg kórtörténetét ismertetik. A Bronchus Carcinoid műtéti eltávolítását követően kialakult májáttétek somatostatinreceptor-expressziójára alapozva, tartós hatású octreotidkezelést, valamint ittriumizotóppal kapcsolt somatostatin-analóg terápiát alkalmaztak. A kezelés megkezdése előtt jelentősen megnövekedett szérumchromogranin-A-szint a kezelések hatására fokozatosan csökkent. A 19 hónapos észlelés időtartama alatt a májáttétek mérete és száma nem növekedett. Következtetés: A szérum-chromogranin-A hatékonyan alkalmazható a hormonálisan inaktív Carcinoid daganatok klinikai követésére. A somatostatin-analógok nemcsak a hormontúltermeléssel járó, hanem a hormonálisan inaktív Carcinoidok esetében is gátolhatják a daganat progresszióját. Introduction: Hormonally inactive Carcinoids represent a significant proportion of all Carcinoids tumours. Classical biochemical and hormonal parameters are not suitable for the diagnosis and follow-up of these tumours. However, the tumour marker chromogranin A that is characteristic for several neuroendocrine tumours and secreted by the majority of these tumours as well, may offer a better means of diagnosis and follow-up. Somatostatin receptors are expressed by hormonally inactive Carcinoids and the presence of these receptors has important diagnostic and therapeutic consequences. Case report: The authors present the history of a patient with a hormonally inactive bronchial Carcinoid tumour. After surgical removal of the bronchial Carcinoid, liver metastases developed which were found to be somatostatin receptor positive. Somatostatin analogue treatment was introduced, followed by Yttrium-isotope labelled somatostatin analogue therapy. Serum chromogranin A was elevated before somatostatin treatment, and gradually decreased in parallel with therapy. The size of liver metastases remained unchanged during treatment. Conclusions: Chromogranin A can be efficiently applied for the clinical follow-up of hormonally inactive Carcinoid tumours. Somatostatin analogues may be effective for preventing tumour progression not only in hormone-secreting but also in hormonally inactive Carcinoid tumours
