Mechanisms of arsenic-induced prolongation of cardiac repolarization.
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.
Ficker
Eckhard
E
Rammelkamp Center, MetroHealth Medical Center, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA. eficker@metrohealth.org
Kuryshev
Yuri A
YA
Dennis
Adrienne T
AT
Obejero-Paz
Carlos
C
Wang
Lu
L
Hawryluk
Peter
P
Wible
Barbara A
BA
Brown
Arthur M
AM
D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D010087:Oxides / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D001152:Arsenicals; D004791:Enzyme Inhibitors; D010087:Oxides; D015221:Potassium Channels; C029341:oxophenylarsine; D000077237:Arsenic Trioxide; D002118:Calcium