Natural products modulating the hERG channel: heartaches and hope

Kratz, Jadel M.; Grienke, Ulrike; Scheel, Olaf; Mann, Stefan A.; Rollinger, Judith M.

doi:10.1039/c7np00014f

Cited by 56 publications

(35 citation statements)

References 158 publications

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“…Natural compounds have been used for the treatment of different anomalies for thousand years [ 78 ]. Plants produce bioactive secondary metabolites that exclusively protect them from predators.…”

Section: Natural Compounds As Possible Therapeutic Solutionmentioning

confidence: 99%

Resveratrol, curcumin, paclitaxel and miRNAs mediated regulation of PI3K/Akt/mTOR pathway: go four better to treat bladder cancer

et al. 2020

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Bladder cancer (BC) is a leading cause of death among urothelial malignancies that more commonly affect male population. Poor prognosis and resistance to chemotherapy are the two most important characteristics of this disease. PI3K/Akt/mTOR signaling pathway has been considered pivotal in the regulation of proliferation, migration, invasiveness, and metastasis. Deregulation of PI3K/Akt/mTOR signaling has been found in 40% of bladder cancers. Several microRNAs (miRNAs) have been reported to interact with the PI3K/Akt/mTOR signaling pathway with a different possible role in proliferation and apoptosis in bladder cancer. Thus, miRNAs can be used as potential biomarkers for BC. Natural compounds have been in the spotlight for the past decade due to their effective anti-proliferative capabilities. However, little is known of its possible effects in bladder cancer. The aim of this review is to discuss the interplay between PI3K/Akt/mTOR, miRNAs, and natural compounds and emphasize the importance of miRNAs as biomarkers and resveratrol, curcumin and paclitaxel as a possible therapeutic approach against bladder cancer.

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Section: Natural Compounds As Possible Therapeutic Solutionmentioning

confidence: 99%

Resveratrol, curcumin, paclitaxel and miRNAs mediated regulation of PI3K/Akt/mTOR pathway: go four better to treat bladder cancer

et al. 2020

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“…However, some antiarrhythmic drugs have been shown in animal models to be highly teratogenic, especially potassium channel blockers (also known as IKr or hERG channel blockers, or class III antiarrhythmics; Danielsson et al 2001). In addition, a significant number of drugs and natural medicines used for treating other conditions have hERG channel-blocking activity as an unwanted side effect (Rampe and Brown 2013;Kratz et al 2017). For this reason, compounds with hERG channel-blocking activity are contraindicated for use during pregnancy (Merino and Perez Silva 2011).…”

Section: Antiarrhythmicsmentioning

confidence: 99%

Environmental Risk Factors for Congenital Heart Disease

Kalisch-Smith

Ved

Sparrow

2019

Cold Spring Harb Perspect Biol

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Congenital heart disease (CHD) has many forms and a wide range of causes. Clinically, it is important to understand the causes. This allows estimation of recurrence rate, guides treatment options, and may also be used to formulate public health advice to reduce the population prevalence of CHD. The recent advent of sophisticated genetic and genomic methods has led to the identification of more than 100 genes associated with CHD. However, despite these great strides, to date only one-third of CHD cases have been shown to have a simple genetic cause. This is because CHD can also be caused by oligogenic factors, environmental factors, and/or gene-environment interaction. Although solid evidence for environmental causes of CHD have been available for almost 80 years, it is only very recently that the molecular mechanisms for these risk factors have begun to be investigated. In this review, we describe the most important environmental CHD risk factors, and what is known about how they cause CHD.

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“…Another key factor that may explain the lack of arrhythmogenic side effects could be the ‘multiple ion channel block effect’ [57], since R -roscovitine also inhibits L-type calcium channels [22]. Indeed, certain drugs bind to more than one voltage-gated ion channel, causing mutually-opposing actions on cardiac action potentials [58]. As a result, the re-classification of R -roscovitine as a Class VI antiarrhythmic agent was recently proposed due to its selective non-peak block of the late I Ca,L current, which likely averts cardiac arrhythmias [59,60].…”

Section: Discussionmentioning

confidence: 99%

The molecular determinants of R-roscovitine block of hERG channels

Cernuda

Fernandes

Allam

et al. 2019

Preprint

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14Human ether-à-go-go-related gene (Kv11.1, or hERG) is a potassium channel that 15 conducts the delayed rectifier potassium current (I Kr ) during the repolarization phase of cardiac 16 action potentials. hERG channels have a larger pore than other K + channels and can trap many 17 unintended drugs, often resulting in acquired LQTS (aLQTS). R-roscovitine, a cyclin-dependent 18 kinase (CDK) inhibitor that also inhibits L-type calcium channels, inhibits open hERG channels 19 but does not become trapped in the pore. Two-electrode voltage clamp recordings from Xenopus 20 oocytes expressing wild-type (WT) or mutant (T623A, S624A, Y652A, F656A) hERG channels 21 demonstrated that, compared to WT hERG, T623A, Y652A, and F656A inhibition by 200 µM R-22 roscovitine was ~ 48 %, 29 %, and 73 % weaker, respectively. In contrast, S624A hERG was 23 inhibited more potently than WT hERG, with an ~ 34 % stronger inhibition. These findings were 24 further supported by the IC 50 values, which were increased for T623A, Y652A and F656A (by 25~5.5, 2.75, and 42 fold respectively) and reduced 1.3 fold for the S624A mutant. Our data 26 suggest that while T623, Y652, and F656 are critical for R-roscovitine-mediated inhibition, S624 27 may not be. This relatively unique feature, coupled with R-roscovitine's tolerance in clinical 28 trials, could guide future drug screens. We discuss our findings and how they lend support for the 29 recent Comprehensive In Vitro Proarrhythmia Assay (CiPA) guidelines on the re-evaluation of 30 potentially useful drugs that had failed testing due to unintended interactions with hERG. 31 32 Introduction 33 Human ether-à-go-go-related gene, or hERG [Kv11.1], is a voltage-gated potassium 34 channel critical for nerve and cardiac function [1,2]. In the heart, hERG channels initially open 3 35 during the depolarization phase of the cardiac action potential (cAP) but immediately inactivate. 36 Upon cAP repolarization, hERG channels de-inactivate and reopen, which allows the ensuing 37 large K + efflux to speed cAP repolarization [1], limit cardiac excitability, and maintain normal 38 QT intervals [3]. Consequently, mutations in hERG are one of the leading causes of congenital 39 long QT syndrome (cLQTS), with a neonatal incidence rate of up to 1 in 2,500 [4]; abnormal 40 cardiac phenotypes are usually triggered during exercise, arousal, or rest [5].41 hERG channels are tetrameric proteins, with each monomer consisting of six 42 transmembrane alpha helices (S1-S6) and cytoplasmic amino and carboxy termini [6]. Similar to 43 other voltage-gated channels, S1-S4 is considered the primary voltage-sensing region, with S4 44 containing positively-charged residues that move slowly outward to induce the characteristically 45 slow activation kinetics of hERG [7,8]. The four S5 and S6 helices and their intervening 46 sections, including the P-loops and P-helices, form the pore and selectivity filter of the channel 47 [9,10]. The pore is thought to have a region between the pore helix and the S6 segments that may 48 provide p...

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Natural products modulating the hERG channel: heartaches and hope

Abstract: This review covers natural products modulating the hERG potassium channel. Risk assessment strategies, structural features of blockers, and the duality target/antitarget are discussed.

Cited by 56 publications

References 158 publications

Resveratrol, curcumin, paclitaxel and miRNAs mediated regulation of PI3K/Akt/mTOR pathway: go four better to treat bladder cancer

Resveratrol, curcumin, paclitaxel and miRNAs mediated regulation of PI3K/Akt/mTOR pathway: go four better to treat bladder cancer

Environmental Risk Factors for Congenital Heart Disease

The molecular determinants of R-roscovitine block of hERG channels

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