Background: Carfilzomib (CFZ) is a second-generation proteasome inhibitor used to treat multiple myeloma. Potent inhibition of the proteasome results in chronic proteotoxic endoplasmic reticulum (ER) stress, leading to apoptosis. While CFZ has improved survival rates in multiple myeloma, it is associated with an increased risk of cardiovascular adverse effects. While this has been putatively linked to cardiotoxicity, CFZ could potentially also exhibit adverse effects on the endothelium.
Objective: To investigate the effects of CFZ on the endothelium METHODS: HUVECs were treated with CFZ and expression of relevant markers of ER stress, inflammation and thrombosis measured and functionally assessed.
Results: CFZ failed to induce ER stress in HUVECs, but induced the expression of KLF-4, eNOS, tPA and thrombomodulin and reduced TNFα mediated ICAM-1 and tissue factor expression, suggesting a potential protective effect on the endothelium. Consistent with these observations, CFZ reduced leukocyte adhesion under shear stress and reduced Factor Xa generation and fibrin clot formation on the endothelium following TNFα treatment and inhibited Von Willebrand Factor (VWF) and Angiopoietin-2 exocytosis from Webiel-Palade bodies. Subsequently CFZ inhibited the formation of VWF-platelet strings and moreover, media derived from myeloma cell lines induced VWF release, a process also inhibited by CFZ.
Conclusion(s): This data demonstrates that CFZ is unable to induce ER stress in confluent resting endothelial cells and can conversely attenuate the pro-thrombotic effects of TNFα on the endothelium. This study suggests that CFZ does not negatively alter HUVECs, and proteasome inhibition of the endothelium may offer a potential way to prevent thrombosis.
Keywords: Endothelium; Inflammation; Multiple Myeloma; Proteasome; Thrombosis.
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