Browsing by Author "Amarh, Enoch"

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    Letrozole targets the human ether-a-go-go-related gene potassium current in glioblastoma
    (Wiley, 2021) Shugg, Tyler; Dave, Nimita; Amarh, Enoch; Assiri, Abdullah A.; Pollok, Karen E.; Overholser, Brian R.; Medicine, School of Medicine
    Aberrant expression of human ether-a-go-go-related gene (hERG) potassium channels has been implicated in the pathophysiology of glioblastoma (GBM). Letrozole has demonstrated efficacy in pre-clinical GBM models. The objective of this research was to assess the potential for hERG inhibition by letrozole to mediate efficacy in GBM. hERG currents were assessed using patch clamp electrophysiology in an overexpression system during treatment with letrozole, exemestane, or vehicle (dimethyl sulfoxide). Relative to vehicle, peak hERG tail current density was reduced when treated with 300 nM and 1 μM letrozole but not when treated with exemestane (up to 1 μM). Cell proliferation was assessed in cultured glioblastoma cell lines (U87 and U373) treated with letrozole, exemestane, doxazosin (hERG blocker), or vehicle. Letrozole, but not exemestane, reduced cell proliferation relative to vehicle in U87 and U373 cells. The associations between expression of hERG (KCNH2), aromatase (CYP19A1), and the estrogen receptors (ESR1 and ESR2) and time to all-cause mortality were assessed in GBM patients within The Cancer Genome Atlas (TCGA) database. hERG expression was associated with reduced overall survival in the TCGA GBM cohort. Future work is warranted to investigate hERG expression as a potential biomarker to predict the therapeutic potential of hERG inhibitors in GBM.
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    Prolonged Exposure to Remdesivir Inhibits the Human Ether-A-Go-Go-Related Gene Potassium Current
    (Wolters Kluwer, 2023-09-01) Amarh, Enoch; Tisdale, James E.; Overholser, Brian R.; Pharmacology and Toxicology, School of Medicine
    Remdesivir, approved for the treatment of COVID-19, has been associated with heart-rate corrected QT interval (QTc) prolongation and torsade de pointes in case reports. However, data are conflicting regarding the ability of remdesivir to inhibit the human ether-a-go-go-related gene (hERG) -related current. The objective of this study was to investigate the effects remdesivir and its primary metabolite, GS-441524, on hERG-related currents. Human embryonic kidney 293 cells stably expressing hERG were treated with various concentrations of remdesivir and GS-441524. The effects of acute and prolonged exposure on hERG-related current were assessed using whole-cell configuration of voltage-clamp protocols. Acute exposure to remdesivir and GS-441524 had no effect on hERG currents and the half-activation voltage (V 1/2 ). Prolonged treatment with 100 nM and 1 µM remdesivir significantly reduced peak tail currents and hERG current density. The propensity for remdesivir to prolong QTc intervals and induce torsade de pointes in predisposed patients warrants further investigation.