Ibrutinib Inhibits BMX-Dependent Endothelial VCAM-1 Expression In Vitro and Pro-Atherosclerotic Endothelial Activation and Platelet Adhesion In Vivo

Effect of antiplatelet agents and tyrosine kinase inhibitors on oxLDL-mediated procoagulant platelet activity

“…17 Furthermore, the efficacy of aspirin versus P2Y 12 inhibitors in personalized aspects of cardiovascular disease is not well established and more novel antiplatelet agents targeting platelet signaling to limit platelet activation has yet to be optimized. [18][19][20] We previously noted increased oxLDL-related proinflammatory and prothrombotic activities in nonhuman primate models of diet-induced obesity, 21,22 where immunoreceptor tyrosine kinase activation motif (ITAM) signaling responses downstream of GPVI, CD36 and Fc-γ receptor pathways involving tyrosine kinases such as BTK offer new therapeutic targets. [22][23][24][25][26] Here, we investigate how oxLDL affects GPVI/ITAM-driven platelet procoagulant activities, and how traditional and more novel antiplatelet therapies affect these platelet responses ex vivo.…”

“…[18][19][20] We previously noted increased oxLDL-related proinflammatory and prothrombotic activities in nonhuman primate models of diet-induced obesity, 21,22 where immunoreceptor tyrosine kinase activation motif (ITAM) signaling responses downstream of GPVI, CD36 and Fc-γ receptor pathways involving tyrosine kinases such as BTK offer new therapeutic targets. [22][23][24][25][26] Here, we investigate how oxLDL affects GPVI/ITAM-driven platelet procoagulant activities, and how traditional and more novel antiplatelet therapies affect these platelet responses ex vivo. Our findings provide insight into how oxLDL enhances platelet GPVI/ITAM responses and informs how clinically relevant antiplatelet agents (e.g., aspirin, ticagrelor)), as well as therapeutic tyrosine kinase inhibitors (e.g., ibrutinib) may effectively limit platelet activity in dyslipidemia.…”

Ibrutinib disrupts blood-tumor barrier integrity and prolongs survival in rodent glioma model

“…Previous studies have shown high BTK expression on glioma cells and ibrutinib’s efficacy to hinder lymphoma and other solid tumors progression through inhibition of the BTK/BMX pathway. Yet, no studies of ibrutinib’s effect on brain endothelium have been published, which could demonstrate a more complete picture of this drugs effects on the tumor microenvironment [ 12 ]. As such, these findings showcasing ibrutinib’s influence of brain endothelial cell–cell integrity and ABCB1 transporter function have larger implications for various neurologic, vascular and oncologic diseases.…”

“…Ibrutinib is an FDA-approved B-cell lymphoma/lymphocytic leukemia agent that inhibits BTK (Bruton tyrosine kinase) activation, leading to decreased B-cell receptor signaling and decreased proliferative potential. In cardiac endothelium, ibrutinib inhibits vascular cell adhesion, platelet aggregation, and the associated inflammatory responses that occur during endothelial cell activation [ 12 ]. Additionally, ibrutinib has properties that favor BBB permeability, with a low molecular weight (440 Da), nonpolar characteristics, and hydrophobicity [ 12 , 13 ].…”

“…In cardiac endothelium, ibrutinib inhibits vascular cell adhesion, platelet aggregation, and the associated inflammatory responses that occur during endothelial cell activation [ 12 ]. Additionally, ibrutinib has properties that favor BBB permeability, with a low molecular weight (440 Da), nonpolar characteristics, and hydrophobicity [ 12 , 13 ]. Previous studies demonstrated its ability to inhibit downstream cell survival pathways, synergize with radiotherapy, impair glioma-derived pericyte coverage, and prolong survival in mouse glioma models when combined with etoposide [ 14 – 16 ].…”