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Molecular Pharmacology

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Research ArticleArticle

Mechanisms of Arsenic-Induced Prolongation of Cardiac Repolarization

Eckhard Ficker, Yuri A. Kuryshev, Adrienne T. Dennis, Carlos Obejero-Paz, Lu Wang, Peter Hawryluk, Barbara A. Wible and Arthur M. Brown
Molecular Pharmacology July 2004, 66 (1) 33-44; DOI: https://doi.org/10.1124/mol.66.1.33
Eckhard Ficker
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Yuri A. Kuryshev
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Adrienne T. Dennis
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Carlos Obejero-Paz
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Lu Wang
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Peter Hawryluk
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Barbara A. Wible
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Arthur M. Brown
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Abstract

Arsenic trioxide (As2O3) 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 As2O3-induced abnormalities of cardiac electrophysiology. Using biochemical and electrophysiological methods, we show that long-term exposure to As2O3 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 μM. In ventricular myocytes, As2O3 increases action potential duration measured at 30 and 90% of repolarization. As2O3 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 As2O3. Our results suggest that calcium-channel antagonists will be useful in normalizing QT prolongation during As2O3 therapy. As2O3 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.

  • Received September 22, 2003.
  • Accepted March 11, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 66 (1)
Molecular Pharmacology
Vol. 66, Issue 1
1 Jul 2004
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Research ArticleArticle

Mechanisms of Arsenic-Induced Prolongation of Cardiac Repolarization

Eckhard Ficker, Yuri A. Kuryshev, Adrienne T. Dennis, Carlos Obejero-Paz, Lu Wang, Peter Hawryluk, Barbara A. Wible and Arthur M. Brown
Molecular Pharmacology July 1, 2004, 66 (1) 33-44; DOI: https://doi.org/10.1124/mol.66.1.33

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Research ArticleArticle

Mechanisms of Arsenic-Induced Prolongation of Cardiac Repolarization

Eckhard Ficker, Yuri A. Kuryshev, Adrienne T. Dennis, Carlos Obejero-Paz, Lu Wang, Peter Hawryluk, Barbara A. Wible and Arthur M. Brown
Molecular Pharmacology July 1, 2004, 66 (1) 33-44; DOI: https://doi.org/10.1124/mol.66.1.33
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