Chaudhari, Umesh ORCID: 0000-0002-7743-4371, Ellis, James K., Wagh, Vilas, Nemade, Harshal, Hescheler, Jurgen, Keun, Hector C. and Sachinidis, Agapios (2017). Metabolite signatures of doxorubicin induced toxicity in human induced pluripotent stem cell-derived cardiomyocytes. Amino Acids, 49 (12). S. 1955 - 1964. WIEN: SPRINGER WIEN. ISSN 1438-2199

Full text not available from this repository.

Abstract

Drug-induced off-target cardiotoxicity, particularly following anti-cancer therapy, is a major concern in new drug discovery and development. To ensure patient safety and efficient pharmaceutical drug development, there is an urgent need to develop more predictive cell model systems and distinct toxicity signatures. In this study, we applied our previously proposed repeated exposure toxicity methodology and performed H-1 NMR spectroscopy-based extracellular metabolic profiling in culture medium of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to doxorubicin (DOX), an anti-cancer agent. Single exposure to DOX did not show alteration in the basal level of extracellular metabolites while repeated exposure to DOX caused reduction in the utilization of pyruvate and acetate, and accumulation of formate compared to control culture medium. During drug washout, only pyruvate showed reversible effect and restored its utilization by hiPSC-CMs. On the other hand, formate and acetate showed irreversible effect in response to DOX exposure. DOX repeated exposure increased release of lactate dehydrogenase (LDH) in culture medium suggesting cytotoxicity events, while declined ATP levels in hiPSC-CMs. Our data suggests DOX perturbed mitochondrial metabolism in hiPSC-CMs. Pyruvate, acetate and formate can be used as metabolite signatures of DOX induced cardiotoxicity. Moreover, the hiPSC-CMs model system coupled with metabolomics technology offers a novel and powerful approach to strengthen cardiac safety assessment during new drug discovery and development.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Chaudhari, UmeshUNSPECIFIEDorcid.org/0000-0002-7743-4371UNSPECIFIED
Ellis, James K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagh, VilasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nemade, HarshalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hescheler, JurgenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keun, Hector C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sachinidis, AgapiosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-209564
DOI: 10.1007/s00726-017-2419-0
Journal or Publication Title: Amino Acids
Volume: 49
Number: 12
Page Range: S. 1955 - 1964
Date: 2017
Publisher: SPRINGER WIEN
Place of Publication: WIEN
ISSN: 1438-2199
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CARDIOTOXICITY; METABOLOMICS; DISEASE; IDENTIFICATION; MITOCHONDRIA; MECHANISMS; DISCOVERY; BIOMARKER; FORMATE; RATSMultiple languages
Biochemistry & Molecular BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/20956

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item