TY  - JOUR
A1  - Neuber, Christin
A1  - Tröster, Tröster, Alix
A1  - Löser, Reik
A1  - Belter, Birgit
A1  - Schwalbe, Harald
A1  - Pietzsch, Jens
T1  - 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
T2  - Molecules
N2  - 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.
KW  - eph receptor tyrosin kinase family
KW  - ephrins
KW  - regioisomers
KW  - tumor angiogenesis
KW  - tumor hypoxia
KW  - tumor perfusion
KW  - tyrosine kinase inhibitors
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/57415
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-574151
SN  - 1420-3049
VL  - 25
IS  - Article 5115
PB  - MDPI
CY  - Basel
ER  -