Abstract
R-flurbiprofen is the non-COX-inhibiting enantiomer of flurbiprofen and is not converted to S-flurbiprofen in human cells. Nevertheless, it reduces extracellular prostaglandin E2 (PGE2) in cancer or immune cell cultures and human extracellular fluid. Here, we show that R-flurbiprofen acts through a dual mechanism: (i) it inhibits the translocation of cPLA2α to the plasma membrane and thereby curtails the availability of arachidonic acid and (ii) R-flurbiprofen traps PGE2 inside of the cells by inhibiting multidrug resistance–associated protein 4 (MRP4, ABCC4), which acts as an outward transporter for prostaglandins. Consequently, the effects of R-flurbiprofen were mimicked by RNAi-mediated knockdown of MRP4. Our data show a novel mechanism by which R-flurbiprofen reduces extracellular PGs at physiological concentrations, particularly in cancers with high levels of MRP4, but the mechanism may also contribute to its anti-inflammatory and immune-modulating properties and suggests that it reduces PGs in a site- and context-dependent manner.
Highlights
Prostaglandins (PGs) are key mediators in the regulation of pain and inflammation, mucosal health, tumor growth, angiogenesis, blood pressure, kidney function, ocular pressure, neurovascular coupling, and glial and neuronal functions [1]
We show that R-flurbiprofen acts through a dual mechanism: (i) it inhibits the translocation of cPLA2α to the plasma membrane and thereby curtails the availability of arachidonic acid and (ii) R-flurbiprofen traps prostaglandin E2 (PGE2) inside of the cells by inhibiting multidrug resistance–associated protein 4 (MRP4, ABCC4), which acts as an outward transporter for prostaglandins
The anti-carcinogenic effects of R-flurbiprofen in mice have been associated in part with the activation of c-Jun-N-terminal kinase, the accumulation of p53 and p75 (NTR) and/or the activation of protein kinase B (PKB/AKT) [3,10,36,37]
Summary
Prostaglandins (PGs) are key mediators in the regulation of pain and inflammation, mucosal health, tumor growth, angiogenesis, blood pressure, kidney function, ocular pressure, neurovascular coupling, and glial and neuronal functions [1]. They are produced in a multi-step process involving cytosolic phospholipase A2 (cPLA2), cyclooxygenase-1 or -2 (COX-1/-2) and subsequent prostaglandin synthases. S-flurbiprofen inhibits COX-1 and -2, but R-flurbiprofen is inactive as a COX-inhibitor Both enantiomers have anti-nociceptive, anti-inflammatory and anti-cancer effects [3,4,5,6]. Effects observed in humans or rats or human cells cannot be attributed to COX inhibition
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