Although inhibition of phosphoinositide 3-kinase (PI3K) is an emerging strategy 
in cancer therapy, we and others have reported that this action can also 
contribute to drug-induced QT prolongation and arrhythmias by increasing cardiac 
late sodium current (INaL). Previous studies in mice implicate the PI3K-α 
isoform in arrhythmia susceptibility. Here, we have determined the effects of 
new anticancer drugs targeting specific PI3K isoforms on INaL and action 
potentials (APs) in mouse cardiomyocytes and Chinese hamster ovary cells (CHO). 
Chronic exposure (10-100 nM; 5-48 hours) to PI3K-α-specific subunit inhibitors 
BYL710 (alpelisib) and A66 and a pan-PI3K inhibitor (BKM120) increased INaL in 
SCN5A-transfected CHO cells and mouse cardiomyocytes. The specific inhibitors 
(10-100 nM for 5 hours) markedly prolonged APs and generated triggered activity 
in mouse cardiomyocytes (9/12) but not in controls (0/6), and BKM120 caused 
similar effects (3/6). The inclusion of water-soluble PIP3, a downstream 
effector of the PI3K signaling pathway, in the pipette solution reversed these 
arrhythmogenic effects. By contrast, inhibition of PI3K-β, -γ, and -δ isoforms 
did not alter INaL or APs. We conclude that inhibition of cardiac PI3K-α is 
arrhythmogenic by increasing INaL and this effect is not seen with inhibition of 
other PI3K isoforms. These results highlight a mechanism underlying potential 
cardiotoxicity of PI3K-α inhibitors.