Inhibition of hERG Potassium Channels by Celecoxib and Its Mechanism

Abstract

BackgroundCelecoxib (Celebrex), a widely prescribed selective inhibitor of cyclooxygenase-2, can modulate ion channels independently of cyclooxygenase inhibition. Clinically relevant concentrations of celecoxib can affect ionic currents and alter functioning of neurons and myocytes. In particular, inhibition of Kv2.1 channels by celecoxib leads to arrhythmic beating of Drosophila heart and of rat heart cells in culture. However, the spectrum of ion channels involved in human cardiac excitability differs from that in animal models, including mammalian models, making it difficult to evaluate the relevance of these observations to humans. Our aim was to examine the effects of celecoxib on hERG and other human channels critically involved in regulating human cardiac rhythm, and to explore the mechanisms of any observed effect on the hERG channels.Methods and ResultsCelecoxib inhibited the hERG, SCN5A, KCNQ1 and KCNQ1/MinK channels expressed in HEK-293 cells with IC50s of 6.0 µM, 7.5 µM, 3.5 µM and 3.7 µM respectively, and the KCND3/KChiP2 channels expressed in CHO cells with an IC50 of 10.6 µM. Analysis of celecoxib's effects on hERG channels suggested gating modification as the mechanism of drug action.ConclusionsThe above channels play a significant role in drug-induced long QT syndrome (LQTS) and short QT syndrome (SQTS). Regulatory guidelines require that all new drugs under development be tested for effects on the hERG channel prior to first administration in humans. Our observations raise the question of celecoxib's potential to induce cardiac arrhythmias or other channel related adverse effects, and make a case for examining such possibilities.

The Role of Potassium Channel Activation in Celecoxib-Induced Analgesic Action

“…For example, the voltage-gated sodium channel in rat retinal neurons [11] and dorsal root ganglia (DRG) neurons [12], [13], the L-type calcium channel in rat pheochromocytoma (PC12) cells [14] and A7r5 rat aortic smooth muscle cells [15], Kv2.1 channels expressed in HEK293 cells [16], cardiac Kv1.5, Kv4.3 and Kv7.1 channels in guinea pig cardiomyocytes [17] and human eag-related gene (HERG) potassium channels [18] were all reported to be inhibited by CXB. In contrast, Kv7.5 currents in rat A7r5 aortic smooth muscle cells can be acutely augmented by CXB [15].…”

COX‐2‐selective inhibitors celecoxib and deracoxib modulate transient receptor potential vanilloid 3 channels

“…They include several voltage‐activated ion channels, which are modulated by celecoxib. For example, Na + currents (Park et al , ; Frolov et al , ), L‐type calcium channels (Zhang et al , ; Brueggemann et al , ), Kv2.1 (Frolov et al , ), Kv1.5, Kv4.3 and Kv7.1 (Macias et al , ) and human eag‐related gene potassium channels (Frolov et al , ) are all inhibited by celecoxib. In contrast, celecoxib increases Kv7.2‐5 currents (Brueggemann et al , ; Du et al , ).…”

A Computational Method for Unveiling the Target Promiscuity of Pharmacologically Active Compounds

“…Furthermore,w e observed that celecoxib blocked both hERG potassium channels [IC 50 = 45 mm, K B = 31 mm ;r eference:t erfenadine (K i = 20 nm)] and voltage-gated Na + (site 2) channels (79 % displacement of the channel activator veratrine by 50 mm celecoxib), thereby resolving partially conflicting reports in the scientific literature. [25,37] Many of the identified affinities are within the same order of magnitude of COX-2 inhibition by celecoxib.O ne might therefore regard celecoxib as a" promiscuous drug", in particular when considering its ability to block cardiac hERG and Na + channels and antagonize b-adrenergic receptors in vitro. [37] Nonselective orexin receptor interactions might increase the reported risk of sleep disorders.…”

“…[25,37] Many of the identified affinities are within the same order of magnitude of COX-2 inhibition by celecoxib.O ne might therefore regard celecoxib as a" promiscuous drug", in particular when considering its ability to block cardiac hERG and Na + channels and antagonize b-adrenergic receptors in vitro. [37] Nonselective orexin receptor interactions might increase the reported risk of sleep disorders. [38] Under the assumption of appropriate pharmacokinetics,these target activities could partially explain some of the clinical observations of cardiovascular incidents after taking medication.…”