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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

Neuber, C.; Tröster, A.; Löser, R.; Belter, B.; Schwalbe, H.; Pietzsch, J.

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 of 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 VEGF, Ang-1, and Akt/PKB, together with the increased expression of TIMP-1 and TGF-2, 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 JAK/STAT, Ras/Raf/MEK, and NFkB.

Keywords: Eph receptor tyrosin kinase family; ephrins; tyrosine kinase inhibitors; regioisomers; tumor angiogenesis; tumor hypoxia; tumor perfusion

Permalink: https://www.hzdr.de/publications/Publ-31524
Publ.-Id: 31524


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