title: Histone Deacetylase Inhibitors Prolong Cardiac Repolarization through Transcriptional Mechanisms.
abstract: Histone deacetylase (HDAC) inhibitors are an emerging class of anticancer agents that modify gene expression by altering the acetylation status of lysine residues of histone proteins, thereby inducing transcription, cell cycle arrest, differentiation, and cell death or apoptosis of cancer cells. In the clinical setting, treatment with HDAC inhibitors has been associated with delayed cardiac repolarization and in rare instances a lethal ventricular tachyarrhythmia known as torsades de pointes. The mechanism(s) of HDAC inhibitor-induced effects on cardiac repolarization is unknown. We demonstrate that administration of structurally diverse HDAC inhibitors to dogs causes delayed but persistent increases in the heart rate corrected QT interval (QTc), an in vivo measure of cardiac repolarization, at timepoints far removed from the Tmax for parent drug and metabolites. Transcriptional profiling of ventricular myocardium from dogs treated with various HDAC inhibitors demonstrated effects on genes involved in protein trafficking, scaffolding and insertion of various ion channels into the cell membrane as well as genes for specific ion channel subunits involved in cardiac repolarization. Extensive in vitro ion channel profiling of various structural classes of HDAC inhibitors (and their major metabolites) by binding and acute patch clamp assays failed to show any consistent correlations with direct ion channel blockade. Drug-induced rescue of an intracellular trafficking-deficient mutant potassium ion channel, hERG (G601S), and decreased maturation (glycosylation) of wild-type hERG expressed by CHO cells in vitro correlated with prolongation of QTc intervals observed in vivo The results suggest that HDAC inhibitor-induced prolongation of cardiac repolarization may be mediated in part by transcriptional changes of genes required for ion channel trafficking and localization to the sarcolemma. These data have broad implications for the development of these drug classes and suggest that the optimal time to assess potentially transcriptionally mediated physiologic effects will be delayed relative to an epigenetic drug's Tmax/Cmax.
authors.affiliation: *Preclinical Safety, Novartis Institutes of Biomedical Research, 100 Technology Square, Cambridge, MA 02139 stanley.spence@novartis.com.
authors.forename: Stan
authors.initials: S
authors.lastname: Spence
authors.affiliation: Preclinical Safety, Novartis Institutes of Biomedical Research, Klybeckstrasse 141, CH-4057, Basel, CH.
authors.forename: Mark
authors.initials: M
authors.lastname: Deurinck
authors.affiliation: Preclinical Safety, Novartis Institutes of Biomedical Research, One Health Plaza, East Hanover, NJ 07936-1080.
authors.forename: Haisong
authors.initials: H
authors.lastname: Ju
authors.affiliation: Preclinical Safety, Novartis Institutes of Biomedical Research, Klybeckstrasse 141, CH-4057, Basel, CH.
authors.forename: Martin
authors.initials: M
authors.lastname: Traebert
authors.affiliation: Oncology Global Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936-1080.
authors.forename: LeeAnne
authors.initials: L
authors.lastname: McLean
authors.affiliation: *Preclinical Safety, Novartis Institutes of Biomedical Research, 100 Technology Square, Cambridge, MA 02139.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Marlowe
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Pharmaceuticals Corporation, Fabrikstrasse 14-3.02.08, Basel, CH.
authors.forename: Corinne
authors.initials: C
authors.lastname: Emotte
authors.affiliation: Preclinical Safety, Novartis Institutes of Biomedical Research, Klybeckstrasse 141, CH-4057, Basel, CH.
authors.forename: Elaine
authors.initials: E
authors.lastname: Tritto
authors.affiliation: Development Sciences, Safety Assessment, Investigative Toxicology, Genentech Inc, 550 Grandview Drive, South San Francisco, CA 94080.
authors.forename: Min
authors.initials: M
authors.lastname: Tseng
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research Inc, 250 Massachusetts Avenue, Cambridge, MA 02139.
authors.forename: Michael
authors.initials: M
authors.lastname: Shultz
authors.affiliation: Preclinical Safety, Novartis Institutes of Biomedical Research, One Health Plaza, East Hanover, NJ 07936-1080.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Friedrichs
mesh_terms: D000818:Animals; D001692:Biological Transport; D004285:Dogs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D014158:Transcription, Genetic
chemical_list: D056572:Histone Deacetylase Inhibitors
keywords: Dog.; HDAC; QTc; ion channel trafficking