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The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma
Sorafenib, a multikinase inhibitor targeting the Ras/Raf/MAPK (mitogen-activated protein kinase) and vascular endothelial growth factor signaling pathways is an established treatment option for patients with advanced-stage hepatocellular carcinoma (HCC); however, despite its clinical benefit, chemor...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450909/ https://www.ncbi.nlm.nih.gov/pubmed/30962952 http://dx.doi.org/10.1038/s41420-019-0165-7 |
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author | Ye, Liangtao Mayerle, Julia Ziesch, Andreas Reiter, Florian P. Gerbes, Alexander L. De Toni, Enrico N. |
author_facet | Ye, Liangtao Mayerle, Julia Ziesch, Andreas Reiter, Florian P. Gerbes, Alexander L. De Toni, Enrico N. |
author_sort | Ye, Liangtao |
collection | PubMed |
description | Sorafenib, a multikinase inhibitor targeting the Ras/Raf/MAPK (mitogen-activated protein kinase) and vascular endothelial growth factor signaling pathways is an established treatment option for patients with advanced-stage hepatocellular carcinoma (HCC); however, despite its clinical benefit, chemoresistance and disease progression eventually occur almost invariably during treatment. Activation of the PI3K/AKT (phosphatidylinositol-3-kinase/serine/threonine kinase) pathway plays a role in the pathogenesis of HCC and may contribute to determine resistance to sorafenib. We thus evaluated in vitro the effects of the combination of sorafenib and copanlisib, a PI3K inhibitor recently approved for clinical use. The effects of copanlisib alone and in combination with sorafenib were assessed in several HCC cell lines by proliferation and colony formation assays, fluorescence-activated cell sorting analyses, and western blot. In addition, sorafenib-resistant cell clones were used. Copanlisib strongly reduced cell viability and colony formation in different native and sorafenib-resistant HCC cell lines by affecting cyclin D1/CDK4/6 signaling and causing cell cycle arrest. Elevation of phosphorylated (p)-AKT was observed upon incubation with sorafenib and was consistently found in six different unstimulated sorafenib-resistant cell clones. Copanlisib counteracted sorafenib-induced phosphorylation of p-AKT and synergistically potentiated its antineoplastic effect. In summary, copanlisib shows potent anticancer activity as a single agent and acts synergistically in combination with sorafenib in human HCC. Combination of sorafenib with copanlisib represents a rational potential therapeutic option for advanced HCC. |
format | Online Article Text |
id | pubmed-6450909 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64509092019-04-08 The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma Ye, Liangtao Mayerle, Julia Ziesch, Andreas Reiter, Florian P. Gerbes, Alexander L. De Toni, Enrico N. Cell Death Discov Article Sorafenib, a multikinase inhibitor targeting the Ras/Raf/MAPK (mitogen-activated protein kinase) and vascular endothelial growth factor signaling pathways is an established treatment option for patients with advanced-stage hepatocellular carcinoma (HCC); however, despite its clinical benefit, chemoresistance and disease progression eventually occur almost invariably during treatment. Activation of the PI3K/AKT (phosphatidylinositol-3-kinase/serine/threonine kinase) pathway plays a role in the pathogenesis of HCC and may contribute to determine resistance to sorafenib. We thus evaluated in vitro the effects of the combination of sorafenib and copanlisib, a PI3K inhibitor recently approved for clinical use. The effects of copanlisib alone and in combination with sorafenib were assessed in several HCC cell lines by proliferation and colony formation assays, fluorescence-activated cell sorting analyses, and western blot. In addition, sorafenib-resistant cell clones were used. Copanlisib strongly reduced cell viability and colony formation in different native and sorafenib-resistant HCC cell lines by affecting cyclin D1/CDK4/6 signaling and causing cell cycle arrest. Elevation of phosphorylated (p)-AKT was observed upon incubation with sorafenib and was consistently found in six different unstimulated sorafenib-resistant cell clones. Copanlisib counteracted sorafenib-induced phosphorylation of p-AKT and synergistically potentiated its antineoplastic effect. In summary, copanlisib shows potent anticancer activity as a single agent and acts synergistically in combination with sorafenib in human HCC. Combination of sorafenib with copanlisib represents a rational potential therapeutic option for advanced HCC. Nature Publishing Group UK 2019-04-05 /pmc/articles/PMC6450909/ /pubmed/30962952 http://dx.doi.org/10.1038/s41420-019-0165-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Ye, Liangtao Mayerle, Julia Ziesch, Andreas Reiter, Florian P. Gerbes, Alexander L. De Toni, Enrico N. The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma |
title | The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma |
title_full | The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma |
title_fullStr | The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma |
title_full_unstemmed | The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma |
title_short | The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma |
title_sort | pi3k inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450909/ https://www.ncbi.nlm.nih.gov/pubmed/30962952 http://dx.doi.org/10.1038/s41420-019-0165-7 |
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