Imatinib inhibits the functional capacity of cultured human monocytes

Abstract

Summary Imatinib is a tyrosine kinase inhibitor that has been reported to specifically inhibit the growth of bcr-abl expressing chronic myeloid leukaemia progenitors. This drug functions by blocking the ATP-binding site of the kinase domain of bcr-abl, and has also been found to inhibit the c-abl, platelet-derived growth factor receptor, ARG and stem cell factor receptor tyrosine kinases. Reports have recently emerged demonstrating that imatinib also inhibits the growth of non-malignant haemopoietic cells. Here, we demonstrate that concentrations of imatinib within the therapeutic dose range inhibit the function of cultured monocytes (CM) from normal donors. A decrease in the response of CM to LPS was observed morphologically and functionally, with CM grown in the presence of imatinib showing decreased pseudopodia formation and inhibition of IL-6 and TNF-α production following LPS stimulation. Imatinib also reduced the ability of M-CSF and GM-CSF stimulated CM to phagocytose zymosan particles, with uptake of non-opsonized zymosan by M-CSF stimulated CM (M-CM) being most affected. M-CM that had been cultured in the presence of imatinib were also impaired in their ability to stimulate responder cells in a mixed lymphocyte reaction. These results demonstrate that human monocytes cultured in the presence of imatinib are functionally impaired, and suggest that imatinib displays inhibitory activity against other kinase(s) that play a role in monocyte/macrophage development.

Quantification of BCR-ABL transcripts in peripheral blood cells and plasma of chronic myeloid leukemia patients at different stages of tyrosine kinase inhibitor treatment response

“…Imatinib mesylate was shown to inhibit the development and maturation of macrophages from bone marrow progenitors [17], as it blocks the functional capacity of interleukin-6 and tumor necrosis factor alpha resulting in the inhibition of macrophage maturation [18].…”

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…These agents cause growth arrest, apoptosis and decreased cell migration in EGFR-expressing basal keratinocytes through inhibition of the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)-Akt and Janus kinase (JAK)-STAT (signal transducer and activator of transcription) pathways 98 . Finally, imatinib has significant but pleiotropic effects on the immune system, including inhibition of T-cell proliferation and activation [99][100][101][102][103] , impaired monocyte 104 and natural killer cell 105 function, and increased antigen presentation by dendritic cells 106 . The target or targets underlying these effects are unclear, but may include ABL1/2 and/or the T-cell-receptor-associated tyrosine kinases ZAP70 and SYK.…”

Imatinib

“…Human monocytes treated with imatinib in vitro had reduced phagocytosis, impaired formation of pseudopodia, and reduced production of proinflammatory cytokines (IL-6, TNF-a) in response to lipopolysaccharide. 41 Thus, imatinib treatment potentially modulates kidney injury through inhibition of monocyte-macrophage proliferation and function.…”