Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment

Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors predominate as first-line therapy options for renal cell carcinoma. When first-line TKI therapy fails due to resistance development, an optimal second-line therapy has not yet been established. The present investigation is directed t...

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Autores principales:	Eva Juengel, Pascal Schnalke, Jochen Rutz, Sebastian Maxeiner, Felix K.-H. Chun, Roman A. Blaheta
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	renal cell carcinoma tyrosine kinase inhibitors endothelial cells resistance second-line Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d658e594097e425e983507c22ab51534
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spelling	oai:doaj.org-article:d658e594097e425e983507c22ab515342021-11-25T16:49:48ZAntiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment10.3390/biomedicines91116302227-9059https://doaj.org/article/d658e594097e425e983507c22ab515342021-11-01T00:00:00Zhttps://www.mdpi.com/2227-9059/9/11/1630https://doaj.org/toc/2227-9059Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors predominate as first-line therapy options for renal cell carcinoma. When first-line TKI therapy fails due to resistance development, an optimal second-line therapy has not yet been established. The present investigation is directed towards comparing the anti-angiogenic properties of the TKIs, sorafenib and axitinib on human endothelial cells (HUVECs) with acquired resistance towards the TKI sunitinib. HUVECs were driven to resistance by continuously exposing them to sunitinib for six weeks. They were then switched to a 24 h or further six weeks treatment with sorafenib or axitinib. HUVEC growth, as well as angiogenesis (tube formation and scratch wound assay), were evaluated. Cell cycle proteins of the CDK-cyclin axis (CDK1 and 2, total and phosphorylated, cyclin A and B) and the mTOR pathway (AKT, total and phosphorylated) were also assessed. Axitinib (but not sorafenib) significantly suppressed growth of sunitinib-resistant HUVECs when they were exposed for six weeks. This axinitib-associated growth reduction was accompanied by a cell cycle block at the G0/G1-phase. Both axitinib and sorafenib reduced HUVEC tube length and prevented wound closure (sorafenib > axitinib) when applied to sunitinib-resistant HUVECs for six weeks. Protein analysis revealed diminished phosphorylation of CDK1, CDK2 and pAKT, accompanied by a suppression of cyclin A and B. Both drugs modulated CDK-cyclin and AKT-dependent signaling, associated either with both HUVEC growth and angiogenesis (axitinib) or angiogenesis alone (sorafenib). Axitinib and sorafenib may be equally applicable as second line treatment options, following sunitinib resistance.Eva JuengelPascal SchnalkeJochen RutzSebastian MaxeinerFelix K.-H. ChunRoman A. BlahetaMDPI AGarticlerenal cell carcinomatyrosine kinase inhibitorsendothelial cellsresistancesecond-lineBiology (General)QH301-705.5ENBiomedicines, Vol 9, Iss 1630, p 1630 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	renal cell carcinoma tyrosine kinase inhibitors endothelial cells resistance second-line Biology (General) QH301-705.5
spellingShingle	renal cell carcinoma tyrosine kinase inhibitors endothelial cells resistance second-line Biology (General) QH301-705.5 Eva Juengel Pascal Schnalke Jochen Rutz Sebastian Maxeiner Felix K.-H. Chun Roman A. Blaheta Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment
description	Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors predominate as first-line therapy options for renal cell carcinoma. When first-line TKI therapy fails due to resistance development, an optimal second-line therapy has not yet been established. The present investigation is directed towards comparing the anti-angiogenic properties of the TKIs, sorafenib and axitinib on human endothelial cells (HUVECs) with acquired resistance towards the TKI sunitinib. HUVECs were driven to resistance by continuously exposing them to sunitinib for six weeks. They were then switched to a 24 h or further six weeks treatment with sorafenib or axitinib. HUVEC growth, as well as angiogenesis (tube formation and scratch wound assay), were evaluated. Cell cycle proteins of the CDK-cyclin axis (CDK1 and 2, total and phosphorylated, cyclin A and B) and the mTOR pathway (AKT, total and phosphorylated) were also assessed. Axitinib (but not sorafenib) significantly suppressed growth of sunitinib-resistant HUVECs when they were exposed for six weeks. This axinitib-associated growth reduction was accompanied by a cell cycle block at the G0/G1-phase. Both axitinib and sorafenib reduced HUVEC tube length and prevented wound closure (sorafenib > axitinib) when applied to sunitinib-resistant HUVECs for six weeks. Protein analysis revealed diminished phosphorylation of CDK1, CDK2 and pAKT, accompanied by a suppression of cyclin A and B. Both drugs modulated CDK-cyclin and AKT-dependent signaling, associated either with both HUVEC growth and angiogenesis (axitinib) or angiogenesis alone (sorafenib). Axitinib and sorafenib may be equally applicable as second line treatment options, following sunitinib resistance.
format	article
author	Eva Juengel Pascal Schnalke Jochen Rutz Sebastian Maxeiner Felix K.-H. Chun Roman A. Blaheta
author_facet	Eva Juengel Pascal Schnalke Jochen Rutz Sebastian Maxeiner Felix K.-H. Chun Roman A. Blaheta
author_sort	Eva Juengel
title	Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment
title_short	Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment
title_full	Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment
title_fullStr	Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment
title_full_unstemmed	Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment
title_sort	antiangiogenic properties of axitinib versus sorafenib following sunitinib resistance in human endothelial cells—a view towards second line renal cell carcinoma treatment
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d658e594097e425e983507c22ab51534
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Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment

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