Blocking of the Human Ether-à-go-go-Related Gene Channel by Imatinib Mesylate

Fu, Xiangwei; Du, Liqing; Zhao, Ning; Xia, Chengkun; Yu, Kunwu; Cheng, Long; Du, Yumin

doi:10.1248/bpb.b12-00778

Cited by 14 publications

(6 citation statements)

References 32 publications

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“…Human embryonic kidney 293 (HEK 293) cells were cultured in the same condition as described above. HEK 293 cells were transiently transfected with appropriate cDNA plasmids using Lipofectamine LTX and PLUS (Invitrogen) method as described previously 50 . The cDNA encoding human Kv1.2 (from Prof. Yingliang Wu, Wuhan University, Wuhan, China), human Kv1.3 (generously provided by Dr. Garcia Maria, Merck & Co. Inc., West Point, PA, USA) and human Kv1.5 (from Prof. Guirong Li, Hongkong University, Hongkong, China) were subcloned into the vector of pIRES2-EGFP (Clontech, USA).…”

Section: Methodsmentioning

confidence: 99%

Lovastatin blocks Kv1.3 channel in human T cells: a new mechanism to explain its immunomodulatory properties

Zhao

Cheng

et al. 2015

Sci Rep

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Lovastatin is a member of Statins, which are beneficial in a lot of immunologic cardiovascular diseases and T cell-mediated autoimmune diseases. Kv1.3 channel plays important roles in the activation and proliferation of T cells, and have become attractive target for immune-related disorders. The present study was designed to examine the block effect of Lovastatin on Kv1.3 channel in human T cells, and to clarify its new immunomodulatory mechanism. We found that Lovastatin inhibited Kv1.3 currents in a concentration- and voltage-dependent manner, and the IC50 for peak, end of the pulse was 39.81 ± 5.11, 6.92 ± 0.95 μM, respectively. Lovastatin also accelerated the decay rate of current inactivation and negatively shifted the steady-state inactivation curves concentration-dependently, without affecting the activation curve. However, 30 μM Lovastatin had no apparent effect on KCa current in human T cells. Furthermore, Lovastatin inhibited Ca2+ influx, T cell proliferation as well as IL-2 production. The activities of NFAT1 and NF-κB p65/50 were down-regulated by Lovastatin, too. At last, Mevalonate application only partially reversed the inhibition of Lovastatin on IL-2 secretion, and the siRNA against Kv1.3 also partially reduced this inhibitory effect of Lovastatin. In conclusion, Lovastatin can exert immunodulatory properties through the new mechanism of blocking Kv1.3 channel.

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Section: Methodsmentioning

confidence: 99%

Lovastatin blocks Kv1.3 channel in human T cells: a new mechanism to explain its immunomodulatory properties

Zhao

Cheng

et al. 2015

Sci Rep

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“…As with many drugs, tyrosine kinase inhibitors (TKIs) are reported to prolong the QT interval ( Strevel et al , 2007 ; Bello et al , 2009 ; Lee et al , 2010 ; Tolcher et al , 2011 ; Dogan et al , 2012 ; Doherty et al , 2013 ; Dong et al , 2013 ; Heath et al , 2013 ; Shah et al , 2013 ). In vitro studies demonstrated that lapatinib and imatinib interact with the phosphorylation of the cardiac hERG channel.…”

mentioning

confidence: 99%

“…In vitro studies demonstrated that lapatinib and imatinib interact with the phosphorylation of the cardiac hERG channel. This results in a reduction of the repolarising current (IKr), which can lead to action potential prolongation and subsequent QT-interval prolongation ( Lee et al , 2010 ; Dong et al , 2013 ).…”

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confidence: 99%

Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors

et al. 2015

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Background:Tyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers.Methods:In this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib.Results:A total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias.Conclusions:These observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.

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“…As mentioned, QT prolongation is more dangerous with bradycardia, so carefully monitoring in patients under the treatment of crizotinib is necessary. According to the formal studies, imatinib could preferentially block the open HERG channel, contributing to QT interval prolongation [ 65 ]. Lapatinib can block the HERG channel in transfected HEK293 cells and prolong the action potential duration [ 66 ], prolonging the QT interval.…”

Section: Novel Antineoplastic Drugsmentioning

confidence: 99%

Anticancer drugs-related QTc prolongation, torsade de pointes and sudden death: current evidence and future research perspectives

et al. 2018

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Anticancer drugs may have proarrhythmic effects including drug-induced QT interval prolongation, which is of particular importance because it can lead to a fatal polymorphic ventricular tachycardia termed torsade de pointes (TdP). QT interval prolongation and TdP are rare life-threatening untoward effects of anticancer therapy, particularly with arsenic trioxides and anthracyclines, and even some novel molecular targeted drugs touted as ‘tumor specific’. Several factors that affect myocardial repolarization can further increase the risk of TdP. This article reviews the mechanism of QT interval prolongation, risk factors for TdP and the QT toxicity of anticancer drugs as well as its management. Specific attention should be paid to high-risk populations such as patients with underlying heart diseases, electrolyte imbalance and bradycardia. To minimize the occurrence of QT interval prolongation and TdP, it is advisable to conduct a careful risk factor assessment before antitumor therapy. To this end, several new biomarkers have been introduced to predict TdP triggering and recent studies have pointed out the potential clinical relevance of genetic testing.

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Blocking of the Human Ether-à-go-go-Related Gene Channel by Imatinib Mesylate

Cited by 14 publications

References 32 publications

Lovastatin blocks Kv1.3 channel in human T cells: a new mechanism to explain its immunomodulatory properties

Lovastatin blocks Kv1.3 channel in human T cells: a new mechanism to explain its immunomodulatory properties

Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors

Anticancer drugs-related QTc prolongation, torsade de pointes and sudden death: current evidence and future research perspectives

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