TY - JOUR T1 - Inhibition of the α-subunit of phosphoinositide 3-kinase (PI3K) in heart increases late sodium current and is arrhythmogenic JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.117.246157 SP - jpet.117.246157 AU - Tao Yang AU - David F Meoli AU - Javid Moslehi AU - Dan M. Roden Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/03/21/jpet.117.246157.abstract N2 - While 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 Q-T prolongation and arrhythmias by increasing cardiac late sodium current (INaL). Previous studies in mice implicate the PI3K-α isoform as the major effector of the INaL action. Here, we have determined the effects of new anticancer drugs targeting specific PI3K isoforms on INaL and action potentials (APs) in mouse cardiomyocytes and CHO cells. Chronic exposure (5-48hours) to specific PI3K-α subunit inhibitors (BYL710 and A66) and a Pan-PI3K inhibitor (BKM120) dramatically increased INaL in SCN5A-transfected CHO cells and mouse cardiomyocytes. The PI3K-α inhibitors (10-100 nM for 5 hours) profoundly prolonged APs and generated triggered activity in drug-treated cardiomyocytes (9/12) but not in controls (0/6). BKM120 caused similar effects in mouse cardiomyocytes (3/6). Including PIP3, a downstream effector of the PI3K signaling pathway, reversed these arrhythmogenic effects in mice. There were no effects with inhibitors of other PI3K isoforms (β, γ, δ). In patients, treatment with BYL719, but not the PI3K-δ inhibitor idelalisib, was associated with a statistically significant 8-ms increase in rate-corrected Q-T interval. 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. ER -