Mechanisms of Arsenic-Induced Prolongation of Cardiac Repolarization

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 M. 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.

Cardiovascular effects of arsenic: clinical and epidemiological findings

“…As exposure in a wide range of levels is consistently associated with QT prolongation -a risk factor for arrhythmia and sudden cardiac death -torsade de pointes (Ficker et al 2004;Mumford et al 2007;Mordukhovich et al 2009;Wang et al 2009), and increased QT dispersion (Wang et al 2010). As may act on QT by increasing cardiac calcium currents (Ficker et al 2004), but no protective effect of calcium-antagonists has been found (Mordukhovich et al 2009) and there are conflicting data on verapamil enhancing or reducing As cardiotoxicity (Zhao et al 2008a;Luong and Rabkin 2009).…”

“…As may act on QT by increasing cardiac calcium currents (Ficker et al 2004), but no protective effect of calcium-antagonists has been found (Mordukhovich et al 2009) and there are conflicting data on verapamil enhancing or reducing As cardiotoxicity (Zhao et al 2008a;Luong and Rabkin 2009). Through the abovementioned mechanisms, As also exerts its direct cytotoxic effects on cardiomyocytes, inducing apoptosis or necrosis (Zhao et al 2008a;Luong and Rabkin 2009); moreover, the myocardium appears to be a sensitive target tissue for As (Roman et al 2011).…”

Arsenic trioxide induces the apoptosis of human breast cancer MCF-7 cells through activation of caspase-3 and inhibition of HERG channels

“…We previously found that as 2 O 3 prolonged the Qt interval and regulated several ion channels in the guinea pig heart (14). in particular, as 2 O 3 was reported to downregulate the protein expression of cardiac potassium channel hErG and to decrease iKr in guinea pig ventricular myocytes (15). the reduced trafficking of hErG channels to the cell surface in patients treated with as 2 O 3 contributed to the induction of Qt prolongation and torsade de pointes (16).…”

Protein trafficking abnormalities: a new mechanism in drug‐induced long QT syndrome

“…This work amplifies the recent report by Rampe and co-workers (Kuryshev et al, 2005), who also showed that low concentrations of pentamidine selectively disrupted protein trafficking and maturation of KCNH2 channels but not of hKv1.5, KvLQT1/minK and Kv4.3 channels, and that in isolated guinea pig ventricular myocytes culture in pentamidine (10 mM) prolonged action potential duration and reduced I Kr . Taken together, these two papers provide clear evidence of a novel mechanism for causing druginduced LQTS; disruption of KCNH2 channel protein trafficking to reduce surface membrane expression of functional channels.For at least one other drug, arsenic trioxide, disruption of normal KCNH2 channel protein processing has been implicated as a mechanism for drug-induced LQTS (Ficker et al, 2004), although arsenic trioxide has also been reported to directly block KCNH2 channels (Drolet et al, 2004). …”

“…For at least one other drug, arsenic trioxide, disruption of normal KCNH2 channel protein processing has been implicated as a mechanism for drug-induced LQTS (Ficker et al, 2004), although arsenic trioxide has also been reported to directly block KCNH2 channels (Drolet et al, 2004).…”