Novel Thienyl-Based Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma
New medical treatments are urgently needed for advanced hepatocellular carcinoma (HCC). Recently, we showed the anticancer effects of novel thiophene-based kinase inhibitors. In this study, we further characterized the antineoplastic effects and modes of action of the two most promising inhibitors,...
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| Format: | Article |
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MDPI AG
2022-05-01
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| Series: | Journal of Personalized Medicine |
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| Online Access: | https://www.mdpi.com/2075-4426/12/5/738 |
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| author | Andi Ma Bernhard Biersack Nils Goehringer Bianca Nitzsche Michael Höpfner |
| author_facet | Andi Ma Bernhard Biersack Nils Goehringer Bianca Nitzsche Michael Höpfner |
| author_sort | Andi Ma |
| collection | DOAJ |
| description | New medical treatments are urgently needed for advanced hepatocellular carcinoma (HCC). Recently, we showed the anticancer effects of novel thiophene-based kinase inhibitors. In this study, we further characterized the antineoplastic effects and modes of action of the two most promising inhibitors, Thio-Iva and Thio-Dam, and compared their effects with the clinically relevant multi-kinase inhibitor, sorafenib, in HCC cells. Crystal violet staining and real-time cell growth monitoring showed pronounced antiproliferative effects in Huh-7 and SNU-449 cells with IC<sub>50</sub> values in the (sub-)micromolar range. Long-term incubation experiments revealed the reduced clonogenicity of Thio-Iva and Thio-Dam-treated HCC cells. LDH-release tests excluded cytotoxicity as an unspecific mode of action of the inhibitors, while flow cytometry analysis revealed a dose-dependent and pronounced G2/M phase cell cycle arrest and cyclin B1 suppression. Additionally, mitochondria-driven apoptosis was observed through the cytosolic increase of reactive oxygen species, a concomitant PARP cleavage, and caspase-3 induction. Both compounds were found to effectively inhibit the capillary tube formation of endothelial EA.hy926 cells in vitro, pointing towards additional antiangiogenic effects. Antiangiogenic and antineoplastic effects were confirmed in vivo by CAM assays. In summary, the thienyl-acrylonitrile derivatives, Thio-Iva and Thio-Dam, exert significant antineoplastic and antiangiogenic effects in HCC cells. |
| first_indexed | 2024-03-10T03:36:42Z |
| format | Article |
| id | doaj.art-71d836dbd1034dabba69ae01f891dd66 |
| institution | Directory Open Access Journal |
| issn | 2075-4426 |
| language | English |
| last_indexed | 2024-03-10T03:36:42Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Personalized Medicine |
| spelling | doaj.art-71d836dbd1034dabba69ae01f891dd662023-11-23T11:43:57ZengMDPI AGJournal of Personalized Medicine2075-44262022-05-0112573810.3390/jpm12050738Novel Thienyl-Based Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular CarcinomaAndi Ma0Bernhard Biersack1Nils Goehringer2Bianca Nitzsche3Michael Höpfner4Institute of Physiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, GermanyOrganic Chemistry 1, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, GermanyInstitute of Physiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, GermanyInstitute of Physiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, GermanyInstitute of Physiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, GermanyNew medical treatments are urgently needed for advanced hepatocellular carcinoma (HCC). Recently, we showed the anticancer effects of novel thiophene-based kinase inhibitors. In this study, we further characterized the antineoplastic effects and modes of action of the two most promising inhibitors, Thio-Iva and Thio-Dam, and compared their effects with the clinically relevant multi-kinase inhibitor, sorafenib, in HCC cells. Crystal violet staining and real-time cell growth monitoring showed pronounced antiproliferative effects in Huh-7 and SNU-449 cells with IC<sub>50</sub> values in the (sub-)micromolar range. Long-term incubation experiments revealed the reduced clonogenicity of Thio-Iva and Thio-Dam-treated HCC cells. LDH-release tests excluded cytotoxicity as an unspecific mode of action of the inhibitors, while flow cytometry analysis revealed a dose-dependent and pronounced G2/M phase cell cycle arrest and cyclin B1 suppression. Additionally, mitochondria-driven apoptosis was observed through the cytosolic increase of reactive oxygen species, a concomitant PARP cleavage, and caspase-3 induction. Both compounds were found to effectively inhibit the capillary tube formation of endothelial EA.hy926 cells in vitro, pointing towards additional antiangiogenic effects. Antiangiogenic and antineoplastic effects were confirmed in vivo by CAM assays. In summary, the thienyl-acrylonitrile derivatives, Thio-Iva and Thio-Dam, exert significant antineoplastic and antiangiogenic effects in HCC cells.https://www.mdpi.com/2075-4426/12/5/738hepatocellular carcinomaanticancer drugstreatmentangiogenesismulti-kinase inhibitor |
| spellingShingle | Andi Ma Bernhard Biersack Nils Goehringer Bianca Nitzsche Michael Höpfner Novel Thienyl-Based Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma Journal of Personalized Medicine hepatocellular carcinoma anticancer drugs treatment angiogenesis multi-kinase inhibitor |
| title | Novel Thienyl-Based Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma |
| title_full | Novel Thienyl-Based Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma |
| title_fullStr | Novel Thienyl-Based Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma |
| title_full_unstemmed | Novel Thienyl-Based Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma |
| title_short | Novel Thienyl-Based Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma |
| title_sort | novel thienyl based tyrosine kinase inhibitors for the treatment of hepatocellular carcinoma |
| topic | hepatocellular carcinoma anticancer drugs treatment angiogenesis multi-kinase inhibitor |
| url | https://www.mdpi.com/2075-4426/12/5/738 |
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