Mechanisms of Arsenic-Induced Prolongation of Cardiac Repolarization
Open Access
- 21 June 2004
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 66 (1), 33-44
- https://doi.org/10.1124/mol.66.1.33
Abstract
Arsenic trioxide (As(2)O(3)) produces dramatic remissions in patients with relapsed or refractory acute promyelocytic leukemia. Its clinical use is burdened by QT prolongation, torsade de pointes, and sudden cardiac death. In the present study, we analyzed the molecular mechanisms leading to As(2)O(3)-induced abnormalities of cardiac electrophysiology. Using biochemical and electrophysiological methods, we show that long-term exposure to As(2)O(3) increases cardiac calcium currents and reduces surface expression of the cardiac potassium channel human ether-a-go-go-related gene (HERG) at clinically relevant concentrations of 0.1 to 1.5 microM. In ventricular myocytes, As(2)O(3) increases action potential duration measured at 30 and 90% of repolarization. As(2)O(3) interferes with hERG trafficking by inhibition of hERG-chaperone complexes and increases calcium currents by a faster cellular process. We propose that an increase in cardiac calcium current and reduced trafficking of hERG channels to the cell surface cause QT prolongation and torsade de pointes in patients treated with As(2)O(3). Our results suggest that calcium-channel antagonists will be useful in normalizing QT prolongation during As(2)O(3) therapy. As(2)O(3) is the first example of a drug that produces hERG liability by inhibition of ion-channel trafficking. Other drugs that interfere with proteins in the processing pathway of cardiac ion channels may be proarrhythmic for similar reasons.Keywords
This publication has 23 references indexed in Scilit:
- Unusual Effects of a QT-Prolonging Drug, Arsenic Trioxide, on Cardiac Potassium CurrentsCirculation, 2004
- Effect of Arsenic Trioxide on QT Interval in Patients With Advanced MalignanciesJournal of Clinical Oncology, 2003
- Prolongation of cardiac repolarization by arsenic trioxideBlood, 2002
- Interaction between the N-terminal and Middle Regions Is Essential for the in Vivo Function of HSP90 Molecular ChaperonePublished by Elsevier BV ,2002
- The Cardiac Sodium Channel: Gating Function and Molecular PharmacologyJournal of Molecular and Cellular Cardiology, 2001
- Induction of oxyradicals by arsenic: Implication for mechanism of genotoxicityProceedings of the National Academy of Sciences of the United States of America, 2001
- Prolongation of the QT Interval and Ventricular Tachycardia in Patients Treated with Arsenic Trioxide for Acute Promyelocytic LeukemiaAnnals of Internal Medicine, 2000
- A Trafficking Checkpoint Controls GABAB Receptor HeterodimerizationNeuron, 2000
- Molecular basis of functional voltage‐gated K+ channel diversity in the mammalian myocardiumThe Journal of Physiology, 2000
- Torsade de Pointes and T‐U Wave Alternans Associated with Arsenic PoisoningPacing and Clinical Electrophysiology, 1990