2. Academic Validation
  3. Downregulation of hERG channel expression by tyrosine kinase inhibitors nilotinib and vandetanib predominantly contributes to arrhythmogenesis

Downregulation of hERG channel expression by tyrosine kinase inhibitors nilotinib and vandetanib predominantly contributes to arrhythmogenesis

  • Toxicol Lett. 2022 Jul 15;365:11-23. doi: 10.1016/j.toxlet.2022.06.001.
Xiaoyan Cui 1,  Jinglei Sun 1,  Congxin Li 2,  Suhua Qiu 1,  Chenxia Shi 1,  Jingtao Ma 3,  Yanfang Xu 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, Hebei Medical University; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang 050017, China.
  • 2 Department of Pharmacy, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China.
  • 3 Department of Cardiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050010, China.
  • 4 Department of Pharmacology, Hebei Medical University; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang 050017, China. Electronic address: [email protected].
PMID: 35680041 DOI: 10.1016/j.toxlet.2022.06.001
Abstract

Cardiotoxicity by tyrosine kinase inhibitors remains an important concern. Nilotinib and vandetanib clinically carry high proarrhythmic risk and the exact mechanism underlying arrhythmogenesis is not fully understood. In this study, we investigated the effects of nilotinib and vandetanib on the abundance of human ether-á-go-go-related gene (hERG) K+ channel and assessed the potential role of acute hERG blockage versus chronic effects in arrhythmogenesis. We found that both nilotinib and vandetanib prolonged the field potential duration reflecting the repolarisation process and induced cellrythmias of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in a time-and concentration-dependent manner after, after chronic exposure. Patch-clamp recordings revealed significant reductions of hERG current densities by nilotinib or vandetanib after chronic incubation with hERG-HEK293 cells in addition to the acute inhibition. Western blot analysis showed that nilotinib and vandetanib decreased mature hERG protein (155-kDa) expression, in a greater extent than that of the immature form (135-kDa). A serum and glucocorticoid kinase 1 (SGK1) activator, C4-ceramide, prevented the nilotinib-and vandetanib-induced hERG protein downregulation and thus the incidence of cellrrhythmias. Taken together, our data demonstrated that the downregulation of hERG channel abundance on the cellular membrane predominantly contributed to the proarrhythmic effect of nilotinib and vandetanib.

Keywords

Arrhythmogenesis; HERG channel; Human induced pluripotent stem cell-derived cardiomyocytes; Tyrosine kinase inhibitors.

Figures
Products