Abstract
Increased prostaglandin E2 (PGE2) levels were detected in mitochondrial disease patient cells harboring nuclear gene mutations in structural subunits of complex I, using a metabolomics screening approach. The increased levels of this principal inflammation mediator normalized following exposure of KH176m, an active redox-modulator metabolite of sonlicromanol (KH176). We next demonstrated that KH176m selectively inhibited lipopolysaccharide (LPS) or interleukin-1β (IL-1β)-induced PGE2 production in control skin fibroblasts. Comparable results were obtained in the mouse macrophage-like cell line RAW264.7. KH176m selectively inhibited mPGES-1 activity, as well as the inflammation-induced expression of mPGES-1. Finally, we showed that the effect of KH176m on mPGES-1 expression is due to the inhibition of a PGE2-driven positive feedback control-loop of mPGES-1 transcriptional regulation. Based on the results obtained we discuss potential new therapeutic applications of KH176m and its clinical stage parent drug candidate sonlicromanol in mitochondrial disease and beyond.
Highlights
Sonlicromanol, a clinical-stage oral drug candidate, has been developed to combat mitochondrial disease
Cyclooxygenase isoforms 1 and 2 (COX-1 and COX-2) enzymes metabolize arachidonic acid (AA) into prostaglandin G2 ( PGG2) and subsequently to prostaglandin H2 (PGH2) by bis-oxygenation and peroxidation reactions, respectively. PGH2 is the common precursor of the four principal bioactive prostaglandins P GD2, PGI2, PGE2, and P GF2α and the prostanoid thromboxane A2 ( TXA2) that are synthetized by cell- and tissue-specific synthases and isomerases (Fig. 1)[7,8,9]
KH176m selectively decreases the elevated level of PGE2 in primary human skin fibroblasts from patients with mitochondrial disease
Summary
Sonlicromanol ( known as KH176), a clinical-stage oral drug candidate, has been developed to combat mitochondrial disease. PGE2 is synthesized from P GH2 by three different P GE2 synthases which are either membranous (mPGES-1, mPGES-2) or cytosolic (cPGES) enzymes[12]. Of these PGE2 synthases, cPGES and mPGES-2 are constitutively expressed in many organs and tissues, whereas mPGES-1, like COX-2, is up-regulated in response to various inflammatory stimuli. PGE2 has been shown to enhance the transcriptional expression of mPGES-1 in combination with inflammatory stimuli revealing a PGE2-mediated positive feedback control loop of the product on its own enzyme. MPGES-1 has been shown to be selectively increased in several types of cancer and is associated with poor p rognoses[7,16,17]
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