KV11.1, NaV1.5, and CaV1.2 Transporter Proteins as Antitarget for Drug Cardiotoxicity

Kowalska, Magdalena; Nowaczyk, Jacek; Nowaczyk, Alicja

doi:10.3390/ijms21218099

Cited by 14 publications

(17 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While most analogues were found not to cause hERG inhibition, they displayed some degree of inhibition of Ca v 1.2 and Na v 1.5 channels in vitro, which are often associated with cardiotoxicity issues. 37 For comparison, we note that the clinically used lidamidine, while clean with respect to the channels examined, has similar properties in cardiomyocytes as do some of the new compounds reported here (entry 2). We have found that aromatic AU analogues bearing para substitution, in addition to leading to increases in potency, have diminished interactions with Ca V 1.2 and Na V 1.5 channels (entries 4–6).…”

Section: Results and Discussionmentioning

confidence: 62%

“…In the course of profiling, it was determined that AU 8918 was not toxic to HEPG2 or THP1 (macrophage) cells but that many close analogues caused changes in cardiomyocyte beat rate, Na + slope, Na + amplitude, and peak width, portending serious cardiotoxicity issues that would preclude development as drugs (Table ). While most analogues were found not to cause hERG inhibition, they displayed some degree of inhibition of Ca v 1.2 and Na v 1.5 channels in vitro, which are often associated with cardiotoxicity issues . For comparison, we note that the clinically used lidamidine, while clean with respect to the channels examined, has similar properties in cardiomyocytes as do some of the new compounds reported here (entry 2).…”

Section: Results and Discussionmentioning

confidence: 64%

See 1 more Smart Citation

In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas

et al. 2022

View full text Add to dashboard Cite

A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis . The structure–activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 ( 1 ), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including 1 , have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Ca v 1.2 and Na v 1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as 5k ( p -benzamide) and 5n ( p -phenylsulfonamide).

show abstract

Section: Results and Discussionmentioning

confidence: 62%

Section: Results and Discussionmentioning

confidence: 64%

In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Furthermore, the IC 50 value is not necessarily related to the arrhythmogenic potential. 63 , 64 Both CQ and HCQ also inhibit L-type calcium currents with IC 50 values of 3–30 μM and 8–90 μM, respectively. 21 , 52 Kir2.1, generating the rectifying potassium current, is also blocked by both agents with IC 50 values of 6 μM for CQ and 30 μM for HCQ.…”

Section: Discussionmentioning

confidence: 99%

Local Anesthetic Like Inhibition of the Cardiac Na+ Channel Nav1.5 by Chloroquine and Hydroxychloroquine

Hage¹,

Vries²,

Leffler³

et al. 2022

JEP

View full text Add to dashboard Cite

Introduction: Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ) are successfully deployed for different diseases beyond the prophylaxis and treatment of malaria. Both substances exhibit antiviral properties and have been proposed for prophylaxis and treatment of COVID-19 caused by SARS-CoV-2. CQ and HCQ cause similar adverse events including life-threatening cardiac arrhythmia generally based on QT-prolongation, which is one of the most reported adverse events for both agents associated with the treatment of COVID-19. Various drugs known to induce QT-prolongation have been proven to exert local anesthetic (LA)-like properties regarding their impact on the cardiac Na + channel Nav1.5. Inhibition of Nav1.5 is considered as the primary mechanism of cardiotoxicity caused by LAs. However, the mechanism of the arrhythmogenic effects of CQ and HCQ related to Nav1.5 has not yet been fully investigated. Therefore, the exact mechanism of how CQ and HCQ affect the sodium currents generated by Nav1.5 need to be further elucidated. Objective: This in vitro study aims to investigate the effects of CQ and HCQ on Nav1.5-generated sodium currents to identify possible LA-like mechanisms that might contribute to their arrhythmogenic properties. Methods: The effects of CQ and HCQ on Nav1.5-generated sodium currents by HEK-293 cells expressing either wild-type human Nav1.5 or mutant Nav1.5 F1760A are measured using the whole-cell patch-clamp technique. Results: Both agents induce a state-dependent inhibition of Nav1.5. Furthermore, CQ and HCQ produce a use-dependent block of Nav1.5 and a shift of fast and slow inactivation. Results of experiments investigating the effect on the LA-insensitive mutant Nav1.5-F1760A indicate that both agents at least in part employ the proposed LA-binding site of Nav1.5 to induce inhibition. Conclusion:This study demonstrated that CQ and HCQ exert LA-typical effects on Nav1.5 involving the proposed LA binding site, thus contributing to their arrhythmogenic properties.

show abstract

“…For mPRα and PGRMC1, an agonist and antagonist compounds have been reported, respectively. On the other hand, for CaV1.2, only antagonist compounds were described, even though cardiotoxicity or neurotoxocity were reported upon its blockade [228,229]. Finally, for GPRC6A, only an agonist has been reported, although an antagonist profile for its targeting could be more useful considering its inflammatory role regarding cytokine release [230].…”

Section: Msrs As Drug Targetsmentioning

confidence: 99%

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

Masi

Racchi

Travelli

et al. 2021

Cells

View full text Add to dashboard Cite

Cancer is one of the most common causes of death worldwide, and its development is a result of the complex interaction of genetic factors, environmental cues, and aging. Hormone-sensitive cancers depend on the action of one or more hormones for their development and progression. Sex steroids and corticosteroids can regulate different physiological functions, including metabolism, growth, and proliferation, through their interaction with specific nuclear receptors, that can transcriptionally regulate target genes via their genomic actions. Therefore, interference with hormones’ activities, e.g., deregulation of their production and downstream pathways or the exposition to exogenous hormone-active substances such as endocrine-disrupting chemicals (EDCs), can affect the regulation of their correlated pathways and trigger the neoplastic transformation. Although nuclear receptors account for most hormone-related biologic effects and their slow genomic responses are well-studied, less-known membrane receptors are emerging for their ability to mediate steroid hormones effects through the activation of rapid non-genomic responses also involved in the development of hormone-sensitive cancers. This review aims to collect pre-clinical and clinical data on these extranuclear receptors not only to draw attention to their emerging role in cancer development and progression but also to highlight their dual role as tumor microenvironment players and potential candidate drug targets.

show abstract

KV11.1, NaV1.5, and CaV1.2 Transporter Proteins as Antitarget for Drug Cardiotoxicity

Cited by 14 publications

References 109 publications

In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas

In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas

Local Anesthetic Like Inhibition of the Cardiac Na+ Channel Nav1.5 by Chloroquine and Hydroxychloroquine

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

Contact Info

Product

Resources

About