Next Article in Journal
Special Issue “Applications of Photoacoustic Spectroscopy”
Next Article in Special Issue
An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors
Previous Article in Journal
Synergistic Antifungal Activity of Chitosan with Fluconazole against Candida albicans, Candida tropicalis, and Fluconazole-Resistant Strains
Article

The Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitor NVP-BHG712: Effects of Regioisomers on Tumor Growth, Perfusion, and Hypoxia in EphB4-Positive A375 Melanoma Xenografts

1
Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany
2
Centre for Biomolecular Magnetic Resonance (BMRZ), Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-University Frankfurt a. M., Max-von-Laue-Strasse 7, 60438 Frankfurt, Germany
3
Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, 01069 Dresden, Germany
*
Author to whom correspondence should be addressed.
H.S. and J.P. share senior authorship.
Academic Editors: Stefan Laufer and Pierre Koch
Molecules 2020, 25(21), 5115; https://doi.org/10.3390/molecules25215115
Received: 16 September 2020 / Revised: 29 October 2020 / Accepted: 1 November 2020 / Published: 3 November 2020
(This article belongs to the Special Issue Small Molecule Inhibitors of Protein Kinases)
In a previous study, EphB4 was demonstrated to be a positive regulator of A375-melanoma growth but a negative regulator of tumor vascularization and perfusion. To distinguish between EphB4 forward and ephrinB2 reverse signaling, we used the commercially available EphB4 kinase inhibitor NVP-BHG712 (NVP), which was later identified as its regioisomer NVPiso. Since there have been reported significant differences between the inhibition profiles of NVP and NVPiso, we compared the influence of NVP and NVPiso on tumor characteristics under the same experimental conditions. Despite the different inhibitory profiles of NVP and NVPiso, the comparative study conducted here showed the same EphB4-induced effects in vivo as in the previous investigation. This confirmed the conclusion that EphB4-ephrinB2 reverse signaling is responsible for increased tumor growth as well as decreased tumor vascularization and perfusion. These results are further substantiated by microarrays showing differences between mock-transfected and EphB4-transfected (A375-EphB4) cells with respect to at least 9 angiogenesis-related proteins. Decreased expression of vascular endothelial growth factor (VEGF), angiotensin 1 (Ang-1), and protein kinase B (Akt/PKB), together with the increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and transforming growth factor beta-2 (TGF-β2), is consistent with the impaired vascularization of A375-EphB4 xenografts. Functional overexpression of EphB4 in A375-EphB4 cells was confirmed by activation of a variety of signaling pathways, including the Janus kinase/signal transducers and activators of transcription (JAK/STAT), rat sarcoma virus/rapidly accelerated fibrosarcoma/mitogen activated protein kinase kinase (Ras/Raf/MEK), and nuclear factor kappa-B (NFkB) pathways. View Full-Text
Keywords: eph receptor tyrosin kinase family; ephrins; tyrosine kinase inhibitors; regioisomers; tumor angiogenesis; tumor hypoxia; tumor perfusion eph receptor tyrosin kinase family; ephrins; tyrosine kinase inhibitors; regioisomers; tumor angiogenesis; tumor hypoxia; tumor perfusion
Show Figures

Graphical abstract

MDPI and ACS Style

Neuber, C.; Tröster, A.; Löser, R.; Belter, B.; Schwalbe, H.; Pietzsch, J. The Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitor NVP-BHG712: Effects of Regioisomers on Tumor Growth, Perfusion, and Hypoxia in EphB4-Positive A375 Melanoma Xenografts. Molecules 2020, 25, 5115. https://doi.org/10.3390/molecules25215115

AMA Style

Neuber C, Tröster A, Löser R, Belter B, Schwalbe H, Pietzsch J. The Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitor NVP-BHG712: Effects of Regioisomers on Tumor Growth, Perfusion, and Hypoxia in EphB4-Positive A375 Melanoma Xenografts. Molecules. 2020; 25(21):5115. https://doi.org/10.3390/molecules25215115

Chicago/Turabian Style

Neuber, Christin, Alix Tröster, Reik Löser, Birgit Belter, Harald Schwalbe, and Jens Pietzsch. 2020. "The Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitor NVP-BHG712: Effects of Regioisomers on Tumor Growth, Perfusion, and Hypoxia in EphB4-Positive A375 Melanoma Xenografts" Molecules 25, no. 21: 5115. https://doi.org/10.3390/molecules25215115

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop