Histone deacetylase inhibitor resminostat in combination with sorafenib counteracts platelet-mediated pro-tumoral effects in hepatocellular carcinoma

Abstract In hepatocellular carcinoma (HCC), blood platelets have been linked to tumor growth, epithelial-to-mesenchymal transition (EMT), extrahepatic metastasis and a limited therapeutic response to the multikinase inhibitor (MKi) sorafenib, the standard of care in advanced HCC for the last decade....

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Autores principales:	Gundula Streubel, Sabine Schrepfer, Hannah Kallus, Ulrike Parnitzke, Tanja Wulff, Frank Hermann, Matthias Borgmann, Svetlana Hamm
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/63cf45130caa44b08d6d2503534da5b2
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spelling	oai:doaj.org-article:63cf45130caa44b08d6d2503534da5b22021-12-02T14:49:26ZHistone deacetylase inhibitor resminostat in combination with sorafenib counteracts platelet-mediated pro-tumoral effects in hepatocellular carcinoma10.1038/s41598-021-88983-12045-2322https://doaj.org/article/63cf45130caa44b08d6d2503534da5b22021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88983-1https://doaj.org/toc/2045-2322Abstract In hepatocellular carcinoma (HCC), blood platelets have been linked to tumor growth, epithelial-to-mesenchymal transition (EMT), extrahepatic metastasis and a limited therapeutic response to the multikinase inhibitor (MKi) sorafenib, the standard of care in advanced HCC for the last decade. Recent clinical data indicated an improved overall survival for sorafenib in combination with the HDAC inhibitor resminostat in a platelet count dependent manner. Here, the impact of platelets on the sorafenib and resminostat drug effects in HCC cells was explored. In contrast to sorafenib, resminostat triggered an anti-proliferative response in HCC cell lines independent of platelets. As previously described, platelets induced invasive capabilities of HCC cells, a prerequisite for extravasation and metastasis. Importantly, the resminostat/sorafenib drug combination, but not the individual drugs, effectively blocked platelet-induced HCC cell invasion. Exploration of the molecular mechanism revealed that the combined drug action led to a reduction of platelet-induced CD44 expression and to the deregulation of several other epithelial and mesenchymal genes, suggesting interference with cell invasion via EMT. In addition, the drug combination decreased phosphorylated ERK level, indicating inhibition of the mitogenic signaling pathway MEK/ERK. Taken together, the resminostat plus sorafenib combination counteracts platelet-mediated cancer promoting effects in HCC cells.Gundula StreubelSabine SchrepferHannah KallusUlrike ParnitzkeTanja WulffFrank HermannMatthias BorgmannSvetlana HammNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gundula Streubel Sabine Schrepfer Hannah Kallus Ulrike Parnitzke Tanja Wulff Frank Hermann Matthias Borgmann Svetlana Hamm Histone deacetylase inhibitor resminostat in combination with sorafenib counteracts platelet-mediated pro-tumoral effects in hepatocellular carcinoma
description	Abstract In hepatocellular carcinoma (HCC), blood platelets have been linked to tumor growth, epithelial-to-mesenchymal transition (EMT), extrahepatic metastasis and a limited therapeutic response to the multikinase inhibitor (MKi) sorafenib, the standard of care in advanced HCC for the last decade. Recent clinical data indicated an improved overall survival for sorafenib in combination with the HDAC inhibitor resminostat in a platelet count dependent manner. Here, the impact of platelets on the sorafenib and resminostat drug effects in HCC cells was explored. In contrast to sorafenib, resminostat triggered an anti-proliferative response in HCC cell lines independent of platelets. As previously described, platelets induced invasive capabilities of HCC cells, a prerequisite for extravasation and metastasis. Importantly, the resminostat/sorafenib drug combination, but not the individual drugs, effectively blocked platelet-induced HCC cell invasion. Exploration of the molecular mechanism revealed that the combined drug action led to a reduction of platelet-induced CD44 expression and to the deregulation of several other epithelial and mesenchymal genes, suggesting interference with cell invasion via EMT. In addition, the drug combination decreased phosphorylated ERK level, indicating inhibition of the mitogenic signaling pathway MEK/ERK. Taken together, the resminostat plus sorafenib combination counteracts platelet-mediated cancer promoting effects in HCC cells.
format	article
author	Gundula Streubel Sabine Schrepfer Hannah Kallus Ulrike Parnitzke Tanja Wulff Frank Hermann Matthias Borgmann Svetlana Hamm
author_facet	Gundula Streubel Sabine Schrepfer Hannah Kallus Ulrike Parnitzke Tanja Wulff Frank Hermann Matthias Borgmann Svetlana Hamm
author_sort	Gundula Streubel
title	Histone deacetylase inhibitor resminostat in combination with sorafenib counteracts platelet-mediated pro-tumoral effects in hepatocellular carcinoma
title_short	Histone deacetylase inhibitor resminostat in combination with sorafenib counteracts platelet-mediated pro-tumoral effects in hepatocellular carcinoma
title_full	Histone deacetylase inhibitor resminostat in combination with sorafenib counteracts platelet-mediated pro-tumoral effects in hepatocellular carcinoma
title_fullStr	Histone deacetylase inhibitor resminostat in combination with sorafenib counteracts platelet-mediated pro-tumoral effects in hepatocellular carcinoma
title_full_unstemmed	Histone deacetylase inhibitor resminostat in combination with sorafenib counteracts platelet-mediated pro-tumoral effects in hepatocellular carcinoma
title_sort	histone deacetylase inhibitor resminostat in combination with sorafenib counteracts platelet-mediated pro-tumoral effects in hepatocellular carcinoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/63cf45130caa44b08d6d2503534da5b2
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Histone deacetylase inhibitor resminostat in combination with sorafenib counteracts platelet-mediated pro-tumoral effects in hepatocellular carcinoma

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