Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer
Chimeric inhibitors, which merge two drug pharmacophores in a single molecule have become a prominent approach for the design of novel anticancer compounds. Here, we examined animacroxam, which combines histone deacetylase (HDAC) inhibitory and cytoskeleton‐interfering pharmacophores, in testicular...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2019-12-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12582 |
| _version_ | 1811316188459827200 |
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| author | Gustav Steinemann Alexandra Dittmer Jacob Schmidt David Josuttis Michael Fähling Bernhard Biersack Nicola Beindorff Eva Jolante Koziolek Rainer Schobert Winfried Brenner Thomas Müller Bianca Nitzsche Michael Höpfner |
| author_facet | Gustav Steinemann Alexandra Dittmer Jacob Schmidt David Josuttis Michael Fähling Bernhard Biersack Nicola Beindorff Eva Jolante Koziolek Rainer Schobert Winfried Brenner Thomas Müller Bianca Nitzsche Michael Höpfner |
| author_sort | Gustav Steinemann |
| collection | DOAJ |
| description | Chimeric inhibitors, which merge two drug pharmacophores in a single molecule have become a prominent approach for the design of novel anticancer compounds. Here, we examined animacroxam, which combines histone deacetylase (HDAC) inhibitory and cytoskeleton‐interfering pharmacophores, in testicular germ cell tumors (TGCT). The effectiveness of animacroxam was compared to that of the commonly applied chemotherapeutic cisplatin as well as the clinically approved HDAC inhibitor vorinostat. The antineoplastic and antiangiogenic effects of animacroxam on TGCT in vivo were assessed through exploratory animal studies and a modified chorioallantoic membrane assay, revealing that animacroxam has significant antitumor activity in TGCT. A novel positron emission tomography/MR‐imaging approach was applied to determine tumor volume and glucose [2‐fluoro‐2‐deoxy‐d‐glucose (18F‐FDG)] uptake in TGCT tumors, revealing reduced glucose uptake in animacroxam‐treated TGCTs and showing a dose‐dependent suppression of glycolytic enzymes, which led to a breakdown in glycolytic energy production. Furthermore, the observed antiangiogenic effects of animacroxam were related to its ability to inhibit endothelial cell–cell communication, as the expression of gap junction‐forming connexin 43 was strongly suppressed, and gap‐junctional intercellular mass transport was reduced. Our data suggest that the chimeric HDAC inhibitor animacroxam may become a promising candidate for the treatment of solid cancers and may serve as an interesting alternative to platinum‐based therapies. |
| first_indexed | 2024-04-13T11:44:24Z |
| format | Article |
| id | doaj.art-d0a6a347bd194f60846e39f66281417c |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-13T11:44:24Z |
| publishDate | 2019-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-d0a6a347bd194f60846e39f66281417c2022-12-22T02:48:13ZengWileyMolecular Oncology1574-78911878-02612019-12-0113122679269610.1002/1878-0261.12582Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancerGustav Steinemann0Alexandra Dittmer1Jacob Schmidt2David Josuttis3Michael Fähling4Bernhard Biersack5Nicola Beindorff6Eva Jolante Koziolek7Rainer Schobert8Winfried Brenner9Thomas Müller10Bianca Nitzsche11Michael Höpfner12Corporate Member of Freie Universität Berlin Berlin Institute of Health Institute of Physiology Humboldt‐Universität zu BerlinCharité – Universitätsmedizin Berlin GermanyCorporate Member of Freie Universität Berlin Berlin Institute of Health Institute of Physiology Humboldt‐Universität zu BerlinCharité – Universitätsmedizin Berlin GermanyCorporate Member of Freie Universität Berlin Berlin Institute of Health Institute of Physiology Humboldt‐Universität zu BerlinCharité – Universitätsmedizin Berlin GermanyCorporate Member of Freie Universität Berlin Berlin Institute of Health Institute of Physiology Humboldt‐Universität zu BerlinCharité – Universitätsmedizin Berlin GermanyCorporate Member of Freie Universität Berlin Berlin Institute of Health Institute of Vegetative Physiology Humboldt‐Universität zu BerlinCharité – Universitätsmedizin Berlin GermanyDepartment of Organic Chemistry University of Bayreuth GermanyCorporate Member of Freie Universität Berlin Berlin Institute of Health Berlin Experimental Radionuclide Imaging Center (BERIC) Humboldt‐Universität zu BerlinCharité – Universitätsmedizin Berlin GermanyCorporate Member of Freie Universität Berlin Berlin Institute of Health Berlin Experimental Radionuclide Imaging Center (BERIC) Humboldt‐Universität zu BerlinCharité – Universitätsmedizin Berlin GermanyDepartment of Organic Chemistry University of Bayreuth GermanyCorporate Member of Freie Universität Berlin Berlin Institute of Health Berlin Experimental Radionuclide Imaging Center (BERIC) Humboldt‐Universität zu BerlinCharité – Universitätsmedizin Berlin GermanyClinic of Internal Medicine IV ‐ Hematology and Oncology Division Universitätsklinikum Halle (Saale) GermanyCorporate Member of Freie Universität Berlin Berlin Institute of Health Institute of Physiology Humboldt‐Universität zu BerlinCharité – Universitätsmedizin Berlin GermanyCorporate Member of Freie Universität Berlin Berlin Institute of Health Institute of Physiology Humboldt‐Universität zu BerlinCharité – Universitätsmedizin Berlin GermanyChimeric inhibitors, which merge two drug pharmacophores in a single molecule have become a prominent approach for the design of novel anticancer compounds. Here, we examined animacroxam, which combines histone deacetylase (HDAC) inhibitory and cytoskeleton‐interfering pharmacophores, in testicular germ cell tumors (TGCT). The effectiveness of animacroxam was compared to that of the commonly applied chemotherapeutic cisplatin as well as the clinically approved HDAC inhibitor vorinostat. The antineoplastic and antiangiogenic effects of animacroxam on TGCT in vivo were assessed through exploratory animal studies and a modified chorioallantoic membrane assay, revealing that animacroxam has significant antitumor activity in TGCT. A novel positron emission tomography/MR‐imaging approach was applied to determine tumor volume and glucose [2‐fluoro‐2‐deoxy‐d‐glucose (18F‐FDG)] uptake in TGCT tumors, revealing reduced glucose uptake in animacroxam‐treated TGCTs and showing a dose‐dependent suppression of glycolytic enzymes, which led to a breakdown in glycolytic energy production. Furthermore, the observed antiangiogenic effects of animacroxam were related to its ability to inhibit endothelial cell–cell communication, as the expression of gap junction‐forming connexin 43 was strongly suppressed, and gap‐junctional intercellular mass transport was reduced. Our data suggest that the chimeric HDAC inhibitor animacroxam may become a promising candidate for the treatment of solid cancers and may serve as an interesting alternative to platinum‐based therapies.https://doi.org/10.1002/1878-0261.12582cancer therapychick chorioallantoic membraneHDAC inhibitorsPET/MR imagingtumor angiogenesis |
| spellingShingle | Gustav Steinemann Alexandra Dittmer Jacob Schmidt David Josuttis Michael Fähling Bernhard Biersack Nicola Beindorff Eva Jolante Koziolek Rainer Schobert Winfried Brenner Thomas Müller Bianca Nitzsche Michael Höpfner Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer Molecular Oncology cancer therapy chick chorioallantoic membrane HDAC inhibitors PET/MR imaging tumor angiogenesis |
| title | Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer |
| title_full | Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer |
| title_fullStr | Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer |
| title_full_unstemmed | Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer |
| title_short | Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer |
| title_sort | antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer |
| topic | cancer therapy chick chorioallantoic membrane HDAC inhibitors PET/MR imaging tumor angiogenesis |
| url | https://doi.org/10.1002/1878-0261.12582 |
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