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, 3:1

First Online: 19 January 2017Received: 03 December 2016Accepted: 07 January 2017DOI: 10.1186-s40959-017-0020-z

Cite this article as: Zhang, Z., Huang, TQ., Nepliouev, I. et al. Cardio-Oncology 2017 3: 1. doi:10.1186-s40959-017-0020-z


BackgroundSinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase ALK-rearranged non-small cell lung cancer NSCLC. We investigated whether crizotinib could influence heart rate HR through direct cardiac effects.

MethodsThe direct effect of crizotinib on HR was studied using ECG analysis of Langendorff-perfused mouse hearts. The whole-cell patch clamp technique was used to measure the effects of crizotinib on the hyperpolarization-activated funny current, If, in mouse sinoatrial node cells SANCs and hyperpolarization-activated cyclic nucleotide-gated channel 4 HCN4 activity in HEK-293 cells stably expressing human HCN4.

ResultsCrizotinib resulted in a dose-dependent reduction in HR in isolated intact mouse hearts with a half maximal inhibitory concentration IC50 of 1.7 ± 0.4 μmol-L. Because ECG analysis revealed that crizotinib 0–5 μmol-L resulted in significant reductions in HR in isolated mouse hearts without changes in PR, QRS, or QT intervals, we performed whole-cell patch clamp recordings of SANCs which showed that crizotinib inhibited If which regulates cardiac pacemaker activity. Crizotinib resulted in diminished current density of HCN4, the major molecular determinant of If, with an IC50 of 1.4 ± 0.3 μmol-L. Crizotinib also slowed HCN4 activation and shifted the activation curve to the left towards more hyperpolarized potentials.

ConclusionsOur results suggest that crizotinib’s effects on HCN4 channels play a significant role in mediating its observed effects on HR.

KeywordsCrizotinib Bradycardia HCN4 Sinoatrial node Non-small cell lung cancer AbbreviationsALKAnaplastic lymphoma kinase


HCN4Hyperpolarization-activated cyclic nucleotide-gated channel 4

HRHeart rate

IC50Half maximal inhibitory concentration

NSCLCNon-small cell lung cancer

RTKReceptor tyrosine kinase

SANCSinoatrial node cell

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Autor: Zhushan Zhang - Tai-Qin Huang - Igor Nepliouev - Hengtao Zhang - Adam S. Barnett - Paul B. Rosenberg - Sai-Hong I. Ou -


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