Anti-inflammatory effects of dabrafenib on polyphosphate-mediated vascular disruption

Abstract

The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Previous studies have reported polyphosphate (PolyP)-mediated vascular inflammatory responses such as disruption of vascular integrity. Dabrafenib is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. This study illustrates drug repositioning with dabrafenib (DAB) for the modulation of PolyP-mediated vascular inflammatory responses in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Dabrafenib suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/or production of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6. Furthermore, dabrafenib demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of dabrafenib on various systemic inflammatory diseases, such as sepsis or septic shock.