Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model
Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current concept of targeting NOTCH is based on using gamma secretase inhibitors (GSI) to regulate the release of the active NOTCH intracellular domain. However, the clinical outcome of GSI remains unsatisfactor...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2017.00319/full |
| _version_ | 1819092135255736320 |
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| author | Rainer Hubmann Wolfgang Sieghart Susanne Schnabl Mohammad Araghi Martin Hilgarth Marlies Reiter Dita Demirtas Peter Valent Peter Valent Christoph Zielinski Christoph Zielinski Ulrich Jäger Ulrich Jäger Medhat Shehata Medhat Shehata |
| author_facet | Rainer Hubmann Wolfgang Sieghart Susanne Schnabl Mohammad Araghi Martin Hilgarth Marlies Reiter Dita Demirtas Peter Valent Peter Valent Christoph Zielinski Christoph Zielinski Ulrich Jäger Ulrich Jäger Medhat Shehata Medhat Shehata |
| author_sort | Rainer Hubmann |
| collection | DOAJ |
| description | Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current concept of targeting NOTCH is based on using gamma secretase inhibitors (GSI) to regulate the release of the active NOTCH intracellular domain. However, the clinical outcome of GSI remains unsatisfactory. Therefore we analyzed human solid tumor derived cell lines for their nuclear NOTCH activity and evaluated the therapeutic potential of the NOTCH2 transactivation inhibitor gliotoxin in comparison to the representative GSI DAPT. Electrophoretic mobility shift assays (EMSA) were used as a surrogate method for the detection of NOTCH/CSL transcription factor complexes. The effect of gliotoxin on cell viability and its clinical relevance was evaluated in vitro and in a melanoma xenograft mouse model. Cell lines derived from melanoma (518A2), hepatocellular carcinoma (SNU398, HCC-3, Hep3B), and pancreas carcinoma (PANC1) express high amounts of nuclear NOTCH2. Gliotoxin efficiently induced apoptosis in these cell lines whereas the GSI DAPT was ineffective. The specificity of gliotoxin was demonstrated in the well differentiated nuclear NOTCH negative cell line Huh7, which was resistant to gliotoxin treatment in vitro. In xenotransplanted 518A2 melanomas, a single day dosing schedule of gliotoxin was well tolerated without any study limiting side effects. Gliotoxin significantly reduced the tumor volume in early (83 mm3 vs. 115 mm3, p = 0.008) as well as in late stage (218 mm3 vs. 576 mm3, p = 0.005) tumor models. In conclusion, NOTCH2 appears to be a key target of gliotoxin in human neoplasias and gliotoxin deserves further evaluation as a potential therapeutic agent in cancer management. |
| first_indexed | 2024-12-21T22:50:48Z |
| format | Article |
| id | doaj.art-5cb20fc27d864c0c9002935297f751e2 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-21T22:50:48Z |
| publishDate | 2017-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-5cb20fc27d864c0c9002935297f751e22022-12-21T18:47:36ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122017-07-01810.3389/fphar.2017.00319263930Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse ModelRainer Hubmann0Wolfgang Sieghart1Susanne Schnabl2Mohammad Araghi3Martin Hilgarth4Marlies Reiter5Dita Demirtas6Peter Valent7Peter Valent8Christoph Zielinski9Christoph Zielinski10Ulrich Jäger11Ulrich Jäger12Medhat Shehata13Medhat Shehata14Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of ViennaVienna, AustriaDepartment of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of ViennaVienna, AustriaDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of ViennaVienna, AustriaDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of ViennaVienna, AustriaDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of ViennaVienna, AustriaDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of ViennaVienna, AustriaDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of ViennaVienna, AustriaDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of ViennaVienna, AustriaDepartment of Medicine I, Ludwig Boltzmann Cluster Oncology, Medical University of ViennaVienna, AustriaDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of ViennaVienna, AustriaComprehensive Cancer Center Vienna, Drug and Target Screening Unit, Medical University of ViennaVienna, AustriaDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of ViennaVienna, AustriaComprehensive Cancer Center Vienna, Drug and Target Screening Unit, Medical University of ViennaVienna, AustriaDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of ViennaVienna, AustriaComprehensive Cancer Center Vienna, Drug and Target Screening Unit, Medical University of ViennaVienna, AustriaDeregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current concept of targeting NOTCH is based on using gamma secretase inhibitors (GSI) to regulate the release of the active NOTCH intracellular domain. However, the clinical outcome of GSI remains unsatisfactory. Therefore we analyzed human solid tumor derived cell lines for their nuclear NOTCH activity and evaluated the therapeutic potential of the NOTCH2 transactivation inhibitor gliotoxin in comparison to the representative GSI DAPT. Electrophoretic mobility shift assays (EMSA) were used as a surrogate method for the detection of NOTCH/CSL transcription factor complexes. The effect of gliotoxin on cell viability and its clinical relevance was evaluated in vitro and in a melanoma xenograft mouse model. Cell lines derived from melanoma (518A2), hepatocellular carcinoma (SNU398, HCC-3, Hep3B), and pancreas carcinoma (PANC1) express high amounts of nuclear NOTCH2. Gliotoxin efficiently induced apoptosis in these cell lines whereas the GSI DAPT was ineffective. The specificity of gliotoxin was demonstrated in the well differentiated nuclear NOTCH negative cell line Huh7, which was resistant to gliotoxin treatment in vitro. In xenotransplanted 518A2 melanomas, a single day dosing schedule of gliotoxin was well tolerated without any study limiting side effects. Gliotoxin significantly reduced the tumor volume in early (83 mm3 vs. 115 mm3, p = 0.008) as well as in late stage (218 mm3 vs. 576 mm3, p = 0.005) tumor models. In conclusion, NOTCH2 appears to be a key target of gliotoxin in human neoplasias and gliotoxin deserves further evaluation as a potential therapeutic agent in cancer management.http://journal.frontiersin.org/article/10.3389/fphar.2017.00319/fullNOTCH2gliotoxinγ-secretase inhibitorsmelanomahepatocellular carcinomapancreas carcinoma |
| spellingShingle | Rainer Hubmann Wolfgang Sieghart Susanne Schnabl Mohammad Araghi Martin Hilgarth Marlies Reiter Dita Demirtas Peter Valent Peter Valent Christoph Zielinski Christoph Zielinski Ulrich Jäger Ulrich Jäger Medhat Shehata Medhat Shehata Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model Frontiers in Pharmacology NOTCH2 gliotoxin γ-secretase inhibitors melanoma hepatocellular carcinoma pancreas carcinoma |
| title | Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model |
| title_full | Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model |
| title_fullStr | Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model |
| title_full_unstemmed | Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model |
| title_short | Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model |
| title_sort | gliotoxin targets nuclear notch2 in human solid tumor derived cell lines in vitro and inhibits melanoma growth in xenograft mouse model |
| topic | NOTCH2 gliotoxin γ-secretase inhibitors melanoma hepatocellular carcinoma pancreas carcinoma |
| url | http://journal.frontiersin.org/article/10.3389/fphar.2017.00319/full |
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