Imatinib as a novel prostaglandin-releasing drug

Prostaglandin (PG) E2 plays important anti-inflammatory roles, by inhibiting cytokine production, e.g. tumor necrosis factor (TNF)-a and chemokines, and protecting the vasculature, gastrointestinal mucosa and the airways. In preparatory experiments we observed that the BCR-ABL kinase inhibitors, imatinib and nilotinib, enhance the biosynthesis of PGE2 eight-fold, and this coincides with the potent inhibitory effect of imatinib and nilotinib on TNF production. These compounds are known as the first line therapy for chronic myeloid leukemia, but they have also been demonstrated to have anti- inflammatory effects in some murine models of inflammation. Most substantially, we observed that the inhibitory effect of imatinib and nilotinib was reversed, after PGE2 biosynthesis had been abolished using cyclooxygenase (COX) inhibitors. Hence, we hypothesize that imatinib family compounds constitute a fundamental novel class of indirect prostaglandin mimetics that might be invaluable novel therapeutics. In the proposed project we will focus on the effects of BCR-ABL kinase inhibitors with respect to (i) the mechanisms involved in the augmented release of PGE2 from human monocytes, macrophages and neutrophils, (ii) their effects on functional responses of leukocytes such as cytokines/chemokines, oxidative burst and leukotriene (LT)B4 production, and leukocyte interaction with endothelial monolayers, and finally (iii) proof-of-concept studies investigating the PGE2- liberating effect of BCR-ABL kinase inhibitors in two in vivo models of inflammation. Hence we expect to propose a fundamentally novel anti-inflammatory strategy based on the increased PG release by imatinib and/or related compounds.

A new mechanism by which imatinib, a drug used to treat chronic myeloid leukemia, can ameliorate inflammation Imatinib is an effective treatment for chronic myeloid leukemia in patients with the Philadelphia chromosome a genetic alteration which leads to a fusion gene called BCR-ABL1, a signaling protein that is always switched on leading to cell division, by inhibiting BCR-ABL kinase. It is also described that imatinib inhibits other signaling proteins. In addition it was shown that imatinib has anti-inflammatory and immunomodulatory effects. Quite a few of this anti- inflammatory and immunomodulatory have also been shown for the prostaglandin (PG)E2. Prostaglandins and eicosanoids are a group of lipid compounds, are derived enzymatically from arachidonic acid, which is located in the cell membrane, via cyclooxygenases PGH2 and terminal synthases (which in the end are responsible for the synthesis of the different prostanoids/eicosanoids), are found in most cells of the body. PGE2 is on one hand regarded as a pro-inflammatory mediator due to its effects on vasodilatation, edema formation and nociception, on the other hand it is well known that PGE2 has anti-inflammatory effects by inhibiting pro-inflammatory cytokine release. Like imatinib, PGE2 is known to ameliorate acute lung injury, asthma brochiale and bronchoconstriction, as experimentally shown. We could demonstrate that the already registered drug imatinib caused an increase in PGE2 which led to reduced pro-inflammatory cytokine production. This was demonstrated in isolated blood cells, in whole blood and most importantly also in patients with chronic myeloid leukemia who received imatinib treatment. In addition to the pronounced increase in PGE2 also other prostaglandins were increased (PGD2 and PGF2a) which was accompanied by decreased levels of thromboxane, an eicosanoid closely related to prostaglandins, and leading to the conclusion that inhibition of the terminal thromboxane synthase leads to a redirection of PGH2 to the other terminal PG synthases. Altogether our results suggests that imatinib potently increases PGE2 synthesis, thereby ameliorating inflammation and this may add to the anti-inflammatory effect of this drug.