Inhibition of mPGES-1 as therapeutic strategy in inflammation and cancer

Abstract

Prostaglandin E2 (PGE2) is an inflammatory and oncogenic lipid mediator. It is mainly formed via metabolism of arachidonic acid by cyclooxygenases (COX-1 and COX-2) and the terminal enzyme microsomal prostaglandin E synthase-1 (mPGES-1). Widely used non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-1 and/or COX-2, resulting in decreased PGE2 production and reduced inflammation. However, NSAIDs block the production of many other lipid mediators that have important physiological and resolving actions, and these drugs cause gastrointestinal bleeding and/or increase the risk for severe cardiovascular events. Selective inhibition of downstream mPGES-1 for reduction in only PGE2 biosynthesis is therefore an anticipated therapeutic strategy. This PhD thesis aims to increase knowledge on mPGES-1 and its inhibition in inflammation and cancer. Cultures of human cells, preclinical animal models, and clinical material from humans were used to study inflammation at the molecular level, specifically after manipulation of prostaglandin production. The main method of analysis was liquid chromatography tandem mass spectrometry (LC-MS/MS).

This thesis showed that prostacyclin and PGE2 are potentially important mediators in human tendon disease (Paper I). Proteomics and lipidomics data suggested differences in cellular protein and lipid profiles upon pharmacological inhibition of mPGES-1 or COX-2 in cancer cells, where inhibition of mPGES-1 potentiated the cytotoxicity of cytostatic drugs in vitro (Paper II). Daily treatment with an mPGES-1 inhibitor suppressed neuroblastoma tumor growth in vivo via decreased angiogenesis, reduced infiltration of cancer-associated fibroblasts, and a shift towards anti-cancer macrophage polarization (Paper III). Lastly, characterization of five new mPGES-1 inhibitors in preclinical models showed decreased swelling in a paw edema assay in rats and reduced norepinephrine-induced vasoconstriction in human arteries ex vivo (Paper IV). In summary, results from this PhD thesis increase knowledge of prostaglandins in pathology and expand the principle of mPGES-1 as a viable target to treat inflammation and cancer.