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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...

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Autores principales: Ye, Liangtao, Mayerle, Julia, Ziesch, Andreas, Reiter, Florian P., Gerbes, Alexander L., De Toni, Enrico N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
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.
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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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