PT - JOURNAL ARTICLE AU - Tao Yang AU - David F. Meoli AU - Javid Moslehi AU - Dan M. Roden TI - Inhibition of the <em>α</em>-Subunit of Phosphoinositide 3-Kinase in Heart Increases Late Sodium Current and Is Arrhythmogenic AID - 10.1124/jpet.117.246157 DP - 2018 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 460--466 VI - 365 IP - 3 4099 - http://jpet.aspetjournals.org/content/365/3/460.short 4100 - http://jpet.aspetjournals.org/content/365/3/460.full SO - J Pharmacol Exp Ther2018 Jun 01; 365 AB - 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.