Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China.
Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, Japan.
PLoS One. 2023 Feb 2;18(2):e0280656. doi: 10.1371/journal.pone.0280656. eCollection 2023.
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 hERG expressing HEK293 cells (hERG-HEK 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-HEK 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. While a mannosidase I inhibitor kifunensine alone reduced IhERG and the reduction was even larger in combined with gemcitabine, kifunensine was without effect on IhERG when hERG-HEK cells were pretreated with gemcitabine for 24 h. In addition, gemcitabine down-regulated fluorescence intensity for hERG potassium channel protein in rat neonatal cardiomyocyte, although hERG mRNA was unchanged. Our results suggest the possible mechanism of arrhythmias caused by gemcitabine revealing a down-regulation of IhERG through the post-translational glycosylation disruption possibly at the early phase of hERG channel glycosylation in the endoplasmic reticulum that alters the electrical excitability of cells.
吉西他滨是一种常用的抗肿瘤药物，用于治疗多种癌症，包括胰腺癌和非小细胞肺癌。虽然吉西他滨引起的心脏毒性已被广泛认识，但导致心律失常的心脏功能障碍的确切机制仍不清楚。本研究旨在通过评估吉西他滨对人快速延迟整流钾通道（hERG 通道）的致心律失常性心脏毒性，从电生理角度进行研究。在异源表达 hERG 的 HEK293 细胞（hERG-HEK 细胞）中，吉西他滨作用 24 小时后而非即刻减少 hERG 通道电流（IhERG）。吉西他滨使 hERG 通道的激活门控特性向超极化方向改变，而失活、去激活或再激活门控特性不受吉西他滨影响。当吉西他滨与衣霉素（一种 N-乙酰葡萄糖胺磷酸转移酶抑制剂）共同作用于 hERG-HEK 细胞时，吉西他滨不能减少 IhERG 或改变激活特性向超极化方向移动。虽然甘露糖苷酶 I 抑制剂 kifunensine 单独减少 IhERG，且与吉西他滨联合时减少程度更大，但当 hERG-HEK 细胞预先用吉西他滨处理 24 小时时，kifunensine 对 IhERG 无影响。此外，吉西他滨下调了新生大鼠心肌细胞 hERG 钾通道蛋白的荧光强度，尽管 hERG mRNA 没有变化。我们的结果提示吉西他滨引起心律失常的可能机制，通过 hERG 通道糖基化的翻译后破坏，可能在 hERG 通道在内质网糖基化的早期阶段下调 IhERG，从而改变细胞的电兴奋性。
