Mechanism of Kv2.1 channel inhibition by a selective COX-2 inhibitor SC-791—modification of gating

Frolov, Roman V.; Ignatova, Irina I.; Singh, Satpal

doi:10.1016/j.brainres.2010.08.062

Cited by 6 publications

(8 citation statements)

References 31 publications

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“…Figure 2 A-C demonstrates that the main effect of SC-791 on the I KS was acceleration of inactivation, though the reduction in the peak I KS indicates that the drug might also alter the activation kinetics, similarly to its action on the human K v 2.1 [13]. The effect of SC-791 on I KS was measured at 50 ms after the onset of a voltage pulse to +40 mV and at the end of 500 ms pulses.…”

Section: Resultsmentioning

confidence: 99%

“…Because different ion channels can be modulated by coxibs via dissimilar mechanisms with different outcomes (reduction or augmentation of a current) and because specialized cells express specific compositions of ion channels, the end effects of the drugs on cell performance are likely to differ even between cells executing the same function. Indeed, Macias and coauthors have shown that celecoxib can prolong action potential duration in mouse cardiac myocytes while shortening it in guinea pig cardiac myocytes [13]. An additional layer of complexity to this picture is added by possible interaction of coxibs with other molecular targets that could alter cell functioning but are not related to ion channels, such as the coxibs' main receptor, COX-2, or carbonic anhydrases [1], [7].…”

Section: Discussionmentioning

confidence: 99%

“…We have recently examined effects of SC-791 on human K v 2.1channels expressed in HEK-293 cells [13]. The compound, used in the experimental setting [14], [15], [16], [17], has been selected for two reasons, an extremely high selectivity for COX-2 (SC-791 inhibits hCOX-2 with an IC 50 of 4 nM and hCOX-1 with an IC 50 of 114 μM [18], a selectivity ratio of 28,500), and its structural similarity to celecoxib [13]. The drug inhibits K v 2.1 via gating modification, but, unlike celecoxib, it does not induce channel block.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Ion Channels and Heart Beat in Drosophila by Selective COX-2 Inhibitor SC-791

Frolov

Singh

2012

PLoS ONE

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Recent findings suggest that modulation of ion channels might be implicated in some of the clinical effects of coxibs, selective inhibitors of cyclooxygenase-2 (COX-2). Celecoxib and its inactive analog 2,5-dimethyl-celecoxib, but not rofecoxib, can suppress or augment ionic currents and alter functioning of neurons and myocytes. To better understand these unexpected effects, we have recently investigated the mechanism of inhibition of human Kv2.1 channels by a highly selective COX-2 inhibitor SC-791. In this study we have further explored the SC-791 action on ion channels and heartbeat in Drosophila, which lacks cyclooxygenases and thus can serve as a convenient model to study COX-2-independent mechanisms of coxibs. Using intracellular recordings in combination with a pharmacological approach and utilizing available Drosophila mutants, we found that SC-791 inhibited voltage-activated K+ and L-type Ca2+ channels in larval body-wall muscles and reduced heart rate in a concentration-dependent manner. Unlike celecoxib and several other K+ channel blockers, SC-791 did not induce arrhythmia. Instead, application of SC-791 resulted in a dramatic slowing of contractions and, at higher concentrations, in progressively weaker contractions with gradual cessation of heartbeat. Isradipine, a selective blocker of L-type Ca2+ channels, showed a similar pattern of heart arrest, though no prolongation of contractions was observed. Ryanodine was the only channel modulating compound of those tested additionally that was capable of slowing contractions. Like SC-791, ryanodine reduced heart rate without arrhythmia. However, it could not stop heartbeat completely even at 500 µM, the highest concentration used. The magnitude of heart rate reduction, when SC-791 and ryanodine were applied together, was smaller than expected for independent mechanisms, raising the possibility that SC-791 might be interfering with excitation-contraction coupling in Drosophila heart.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of Ion Channels and Heart Beat in Drosophila by Selective COX-2 Inhibitor SC-791

Frolov

Singh

2012

PLoS ONE

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“…On a general note, previous studies have established that ion channel inhibition is not a generic feature of coxibs, but rather that of celecoxib and some other structurally similar compounds not used in therapeutics [2], [4], [9]. Out of the four prescribed coxibs, effects on ion channels of only two of them, celecoxib and rofecoxib, have been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…We have shown that celecoxib can directly inhibit K + channels in fruit flies, and K + and Na + channels in mammals, with strong effects on cardiomyocyte and neuronal function [6], [7]. We have also shown that celecoxib and SC-791 (a highly selective COX-2 inhibitor) can inhibit K v 2.1 channels expressed in HEK-293 cells via modification of gating and channel block [8], [9]. In addition, it has been reported that celecoxib and its inactive analog, 2,5-dimethyl-celecoxib (DMC), but not rofecoxib, can acutely and reversibly up-regulate currents through K v 7.5 (KCNQ5) cardiac channels, while inhibiting other currents [4].…”

Section: Introductionmentioning

confidence: 96%

Inhibition of hERG Potassium Channels by Celecoxib and Its Mechanism

2011

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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.

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Protein kinase CK2 promotes cancer cell viability via up‐regulation of cyclooxygenase‐2 expression and enhanced prostaglandin E2 production

Yefi

Ponce

Niechi

et al. 2011

J of Cellular Biochemistry

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Augmented expression of protein kinase CK2 is associated with hyperproliferation and resistance to apoptosis in cancer cells. Effects of CK2 are at least partially linked to signaling via the Wnt/β-catenin pathway, which is dramatically enhanced in colon cancer. Cyclooxygenase-2 (COX-2), a Wnt/β-catenin target gene, has been associated with enhanced cancer progression and metastasis. However, the possibility that a connection may exist between CK2 and COX-2 has not been explored previously. Here we investigated changes in COX-2 expression and activity upon CK2 modulation and evaluated how these changes affected cell viability. COX-2 expression and cell viability decreased upon selective inhibition of COX-2 with SC-791 or CK2 with 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), both in human colon (HT29-ATCC, HT29-US, DLD-1) and breast (ZR-75) cancer cells, as well as in human embryonic kidney (HEK-293T) cells. On the other hand, ectopic CK2α expression promoted up-regulation of COX-2 by activating the Wnt/β-catenin pathway in HEK-293T cells. Noteworthy, over-expression of either CK2α, β-catenin or COX-2, as well as supplementation of the medium with prostaglandin E2 (PGE2), all were individually sufficient to overcome limitations in cell viability triggered by CK2 inhibition either upon addition of DMAT or over-expression of a dominant negative CK2α variant. Altogether, these findings provide new insight to the role of CK2 in cancer by up-regulating COX-2 expression and thereby PGE2 production.

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Mechanism of Kv2.1 channel inhibition by a selective COX-2 inhibitor SC-791—modification of gating

Cited by 6 publications

References 31 publications

Inhibition of Ion Channels and Heart Beat in Drosophila by Selective COX-2 Inhibitor SC-791

Inhibition of Ion Channels and Heart Beat in Drosophila by Selective COX-2 Inhibitor SC-791

Inhibition of hERG Potassium Channels by Celecoxib and Its Mechanism

Protein kinase CK2 promotes cancer cell viability via up‐regulation of cyclooxygenase‐2 expression and enhanced prostaglandin E2 production

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