Journal article

Publication year: 2021

Journal: International Journal of Molecular Sciences

Volume number: 22

Issue number: 3

eISSN: 1422-0067

Open access status: Gold

DOI Link: https://doi.org/10.3390/ijms22031502

Publisher: MDPI

Abstract: 
Pulmonary hypertension (PH) is characterized by a progressive elevation of mean arterial pressure followed by right ventricular failure and death. Previous studies have indicated that numerous inhibitors of receptor tyrosine kinase signaling could be either beneficial or detrimental for the treatment of PH. Here we investigated the therapeutic potential of the multi-kinase inhibitor regorafenib (BAY 73-4506) for the treatment of PH. A peptide-based kinase activity assay was performed using the PamStation(R)12 platform. The 5-bromo-2 '-deoxyuridine proliferation and transwell migration assays were utilized in pulmonary arterial smooth muscle cells (PASMCs). Regorafenib was administered to monocrotaline- and hypoxia-induced PH in rats and mice, respectively. Functional parameters were analyzed by hemodynamic and echocardiographic measurements. The kinase activity assay revealed upregulation of twenty-nine kinases in PASMCs from patients with idiopathic PAH (IPAH), of which fifteen were established as potential targets of regorafenib. Regorafenib showed strong anti-proliferative and anti-migratory effects in IPAH-PASMCs compared to the control PASMCs. Both experimental models indicated improved cardiac function and reduced pulmonary vascular remodeling upon regorafenib treatment. In lungs from monocrotaline (MCT) rats, regorafenib reduced the phosphorylation of c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2. Overall, our data indicated that regorafenib plays a beneficial role in experimental PH.

Harvard Citation style: Veeroju, S., Kojonazarov, B., Weiss, A., Ghofrani, H., Weissmann, N., Grimminger, F., et al. (2021) Therapeutic Potential of Regorafenib-A Multikinase Inhibitor in Pulmonary Hypertension, International Journal of Molecular Sciences, 22(3), Article 1502. https://doi.org/10.3390/ijms22031502

APA Citation style: Veeroju, S., Kojonazarov, B., Weiss, A., Ghofrani, H., Weissmann, N., Grimminger, F., Seeger, W., Novoyatleva, T., & Schermuly, R. (2021). Therapeutic Potential of Regorafenib-A Multikinase Inhibitor in Pulmonary Hypertension. International Journal of Molecular Sciences. 22(3), Article 1502. https://doi.org/10.3390/ijms22031502