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 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.

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Author:Eva JüngelORCiDGND, Pascal SchnalkeGND, Jochen RutzGND, Sebastian MaxeinerGND, Felix ChunORCiDGND, Roman A. BlahetaORCiD
URN:urn:nbn:de:hebis:30:3-692732
DOI:https://doi.org/10.3390/biomedicines9111630
ISSN:2227-9059
Parent Title (English):Biomedicines
Publisher:MDPI
Place of publication:Basel
Document Type:Article
Language:English
Date of Publication (online):2021/11/06
Date of first Publication:2021/11/06
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/01/23
Tag:endothelial cells; renal cell carcinoma; resistance; second-line; tyrosine kinase inhibitors
Volume:9
Issue:11. art. 1630
Article Number:1630
Page Number:14
First Page:1
Last Page:14
Note:
This research was funded by Wilhelm Sander-Stiftung, München, Germany, grant number 2015.020.1.
Note:
Gefördert durch den Open-Access-Publikationsfonds der Goethe-Universität
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International