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Inhibition of the -Subunit of Phosphoinositide 3-Kinase in Heart Increases Late Sodium Current and Is Arrhythmogenic.

Yang T, Meoli DF, Moslehi J, Roden DM
J Pharmacol Exp Ther. 2018 365 (3): 460-466

PMID: 29563327 · PMCID: PMC5931436 · DOI:10.1124/jpet.117.246157

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 (I). Previous studies in mice implicate the PI3K- isoform in arrhythmia susceptibility. Here, we have determined the effects of new anticancer drugs targeting specific PI3K isoforms on I and action potentials (APs) in mouse cardiomyocytes and Chinese hamster ovary cells (CHO). Chronic exposure (10-100 nM; 5-48 hours) to PI3K--specific subunit inhibitors BYL710 (alpelisib) and A66 and a pan-PI3K inhibitor (BKM120) increased I in -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-, -, and - isoforms did not alter I or APs. We conclude that inhibition of cardiac PI3K- is arrhythmogenic by increasing I and this effect is not seen with inhibition of other PI3K isoforms. These results highlight a mechanism underlying potential cardiotoxicity of PI3K- inhibitors.

Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

MeSH Terms (15)

Action Potentials Animals Arrhythmias, Cardiac CHO Cells Cricetulus Dose-Response Relationship, Drug Electrophysiological Phenomena Enzyme Inhibitors Female Heart Mice Mice, Inbred C57BL Myocytes, Cardiac Phosphoinositide-3 Kinase Inhibitors Sodium

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