TITLE:
Use of Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters to Assess Potential for Chronic Treatment with Compounds to Cause QT Prolongation
AUTHORS:
Taro Hihara, Kazuto Yamazaki, Tomohiko Taniguchi, Takashi Yoshinaga, Masashi Ito, Kohei Sawada
KEYWORDS:
Human Embryonic Stem Cell-Derived Cardiomyocytes; Field Potential Duration; QT Prolongation; Chronic Treatment; Risk Assessment
JOURNAL NAME:
Pharmacology & Pharmacy,
Vol.5 No.4,
April
9,
2014
ABSTRACT: Drug-induced
QT prolongation is a serious clinical issue in developing novel drug candidates
and marketing drugs. A major cause of QT prolongation is direct inhibition of human ether-à-go-go-related gene (hERG)
channels. Reduction in repolarization-related channel expression levels on
plasma membranes is another mechanism that induces QT prolongation. Recently,
we established a system for assessing the risk of QT prolongation by using
human embryonic stem cell-derived cardiomyocyte clusters (hES-CMCs) in which
the field potential duration (FPD) or corrected FPD (FPDc) was measured as an
indicator of drug-induced QT interval prolongation. Here, we examined whether this
system was able to detect FPDc prolongation caused by pentamidine or probucol,
both of which can induce QT prolongation after long-term treatment. hES-CMCs
were treated with pentamidine or probucol, and the FPDc of the same clusters
was measured 10 min, 4 h, and 24 h after the start of treatment. Concentration-dependent
FPDc prolongation was observed at 24 h, but not at 10 min, with pentamidine or
probucol treatment. These results suggest that the hES-CMC-based assessment
system can be used to detect both acute (at 10 min) and delayed (at 24 h) QT
prolongation risk on the same platform by simple alteration of the extended
culture period.