Universität zu Köln

Jacob, Fabian, Yonis, Amina Y., Cuello, Friederike, Luther, Pradeep ORCID: 0000-0002-8841-4368, Schulze, Thomas, Eder, Alexandra, Streichert, Thomas, Mannhardt, Ingra, Hirt, Marc N., Schaaf, Sebastian, Stenzig, Justus, Force, Thomas ORCID: 0000-0002-0450-8659, Eschenhagen, Thomas and Hansen, Arne (2016). Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue. PLoS One, 11 (2). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Introduction Left ventricular dysfunction is a frequent and potentially severe side effect of many tyrosine kinase inhibitors (TKI). The mode of toxicity is not identified, but may include impairment of mitochondrial or sarcomeric function, autophagy or angiogenesis, either as an on-target or off-target mechanism. Methods and Results We studied concentration-response curves and time courses for nine TKIs in three-dimensional, force generating engineered heart tissue (EHT) from neonatal rat heart cells. We detected a concentration-and time-dependent decline in contractile force for gefitinib, lapatinib, sunitinib, imatinib, sorafenib, vandetanib and lestaurtinib and no decline in contractile force for erlotinib and dasatinib after 96 hours of incubation. The decline in contractile force was associated with an impairment of autophagy (LC3 Western blot) and appearance of autophagolysosomes (transmission electron microscopy). Conclusion This study demonstrates the feasibility to study TKI-mediated force effects in EHTs and identifies an association between a decline in contractility and inhibition of autophagic flux.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Jacob, Fabian UNSPECIFIED UNSPECIFIED UNSPECIFIED Yonis, Amina Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cuello, Friederike UNSPECIFIED UNSPECIFIED UNSPECIFIED Luther, Pradeep UNSPECIFIED orcid.org/0000-0002-8841-4368 UNSPECIFIED Schulze, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Eder, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Streichert, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Mannhardt, Ingra UNSPECIFIED UNSPECIFIED UNSPECIFIED Hirt, Marc N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaaf, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Stenzig, Justus UNSPECIFIED UNSPECIFIED UNSPECIFIED Force, Thomas UNSPECIFIED orcid.org/0000-0002-0450-8659 UNSPECIFIED Eschenhagen, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansen, Arne UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-284788
DOI:	10.1371/journal.pone.0145937
Journal or Publication Title:	PLoS One
Volume:	11
Number:	2
Date:	2016
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INDUCED CARDIOTOXICITY; CELL-DEATH; IN-VITRO; IMATINIB; MITOCHONDRIA; MECHANISMS; SUNITINIB; AUTOPHAGY; CARDIOMYOCYTES; SORAFENIB Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28478