Unusual Effects of a QT-Prolonging Drug, Arsenic Trioxide, on Cardiac Potassium Currents

Abstract

Background-Cases of QT prolongation, torsades de pointes, and sudden death have been reported with arsenic trioxide (As 2 O 3 ), a highly effective agent for acute promyelocytic leukemia. In this study, we evaluated the effects of As 2 O 3 on repolarizing cardiac ion currents. Methods and Results-In HERG-or KCNQ1ϩKCNE1-transfected CHO cells (nϭ32; total), As 2 O 3 caused concentrationdependent block of both I Kr and I Ks , with an IC 50 for tail current block of 0.14Ϯ0.01 mol/L for I Kr and 1.13Ϯ0.06 mol/L for I Ks . In contrast to other QT-prolonging drugs, As 2 O 3 also activated a time-independent current that additional experiments identified as I K-ATP . Conclusions-As 2 O 3 blocks both I Kr and I Ks at clinically relevant concentrations. On the other hand, it also activates I K-ATP , which maintains normal repolarization. We infer that variability in the extent of QT interval prolongation and onset of ventricular arrhythmias during arsenic therapy represents competing effects to block and activate multiple repolarizing potassium currents. Key Words: torsades de pointes Ⅲ drugs Ⅲ ion channels A pproximately 20% to 30% of patients with acute promyelocytic leukemia (APL) relapse with current standard all-trans retinoic acid and anthracycline-based chemotherapy regimen. 1 In the mid-1990s, studies from China reported that arsenic trioxide (As 2 O 3 ) achieved complete remission in as many as 90% of patients with APL, 2,3 and additional trials have confirmed these results. 4,5 However, treatment has also been associated with QT prolongation, torsades de pointes, and sudden death. 4,6 -8 Because most of the patients receiving As 2 O 3 have been exposed to cardiotoxic chemotherapy, cardiac dysfunction is thought to be universal before As 2 O 3 therapy begins. 6,9 In addition, hypokalemia and hypomagnesemia are among the most common As 2 O 3 -related side effects. 1 Thus, it has been proposed that QT prolongation and ventricular arrhythmias associated with arsenic could be exacerbated by concurrent electrolyte disturbances or previous chemotherapy-induced cardiac damage. 4,6 -8 Recently, clinically relevant concentrations of As 2 O 3 (1 to 10 mol/L) have been reported to prolong the action potential duration in guinea pig papillary muscle. 9 In another study using rabbit hearts, polymorphic ventricular tachycardia was observed with As 2 O 3 30 mol/L. 10 In this study, we therefore investigated the effects of As 2 O 3 on cardiac repolarizing currents and identified an unexpectedly complex profile that may underlie variability in the arrhythmogenic potential of arsenic. MethodsExperiments were performed in CHO cells transfected with 2 g (each) of HERG, KCNQ1ϩKCNE1, or Kir6.2ϩSUR2A cDNAs. Kir6.2 and SUR2A cDNAs were kindly provided by Dr Joseph Bryan, Baylor College of Medicine, Houston, Tex. Cells were transfected using FuGENE 6 (Roche Applied Science). Green fluorescent protein (GFP) was coexpressed to identify transfected cells. All whole cell currents were recorded at 22°C to 23°C. Cells were held at Ϫ80 mV an...

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).…”

The Evaluation of the Ameliorative Effect of Montelukast Against Arsenic Trioxide-Induced Cardiotoxicity in Rats

“…In another study, the prevalence of QTc prolongation in arsenic-exposed people was reported as 90% (24) and the underlying mechanisms of arsenic cardiotoxicity have been suggested as excessive generation of oxygen free radicals and oxidative stress (6,24).…”

Monomorphic ventricular tachycardia caused by arsenic trioxide therapy for acute promyelocytic leukaemia

“…1,3 The prolongation of the QTc interval appears to be due to a concentration-dependent blockade of IKr and IKs potassium currents compromising repolarisation and increasing electrical susceptibility to ventricular arrhythmias. 4 Arsenic has also been shown to activate a time-independent IK-ATP which maintains normal repolarisation. The variability in QTc prolongation as well as the onset of ventricular arrhythmias likely represent competing activation and blockade of potassium channels during ventricular repolarisation.…”

“…The variability in QTc prolongation as well as the onset of ventricular arrhythmias likely represent competing activation and blockade of potassium channels during ventricular repolarisation. 4 The susceptibility for ventricular pro-arrhythmia has been postulated to be linked to electrolyte abnormalities, specifically hypokalaemia and hypomagnesaemia, as well as concomitant treatment with QTc-prolonging medications.…”