Key result
Gemcitabine suppresses hERG current at ~0.16 µM, suggesting a mechanism for its proarrhythmic cardiotoxicity.
Why the study?
Although gemcitabine-induced cardiotoxicity is widely recognized, the exact mechanism of cardiac dysfunction causing arrhythmias remains unclear.
Does gemcitabine alter hERG channel current and gating properties in HEK293 cells?
Does gemcitabine alter hERG channel current and gating properties in HEK293 cells?
Gemcitabine may cause proarrhythmic cardiotoxicity by down-regulating hERG current through the disruption of post-translational glycosylation.
May warrant QT monitoring in gemcitabine recipients; leaves open clinical arrhythmia risk pending human data.
Gemcitabine is an antineoplastic drug commonly used in the treatment of several types of cancers including pancreatic cancer and non–small cell lung cancer. Although gemcitabine-induced cardiotoxicity is widely recognized, the exact mechanism of cardiac dysfunction causing arrhythmias remains unclear. The objective of this study was to electrophysiologically evaluate the proarrhythmic cardiotoxicity of gemcitabine focusing on the human rapid delayed rectifier potassium channel, hERG channel. In heterologous expression system in HEK293 cells, hERG channel current (IhERG) was reduced by gemcitabine when applied for 24 h but not immediately after the application. Gemcitabine modified the activation gating properties of the hERG channel toward the hyperpolarization direction, while inactivation, deactivation or reactivation gating properties were unaffected by gemcitabine. When gemcitabine was applied to hERG-expressing HEK293 cells in combined with tunicamycin, an inhibitor of N-acetylglucosamine phosphotransferase, gemcitabine was unable to reduce IhERG or shift the activation properties toward the hyperpolarization direction. Our results suggest the possible mechanism of arrhythmias caused by gemcitabine revealing a down-regulation of IhERG through the post-translational glycosylation disruption that alters the electrical excitability of cells.
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Wei et al. (2021) studied Cardiotoxicity. Gemcitabine vs. Vehicle was evaluated on hERG channel current (IhERG) suppression (EC50 0.16 µM). Gemcitabine applied for 24 hours reduced hERG channel current with an EC50 of 0.16 µM and shifted activation gating toward hyperpolarization, suggesting a mechanism for its proarrhythmic cardiotoxicity.
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