Universität zu Köln

Nemade, Harshal, Chaudhari, Umesh ORCID: 0000-0002-7743-4371, Acharya, Aviseka, Hescheler, Juergen, Hengstler, Jan Georg, Papadopoulos, Symeon and Sachinidis, Agapios (2018). Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch. Toxicol., 92 (4). S. 1507 - 1525. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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Abstract

Etoposide (ETP) and anthracyclines are applied for wide anti-cancer treatments. However, the ETP-induced cardiotoxicity remains to be a major safety issue and the underlying cardiotoxic mechanisms are not well understood. This study is aiming to unravel the cardiotoxicity profile of ETP in comparison to anthracyclines using physiologically relevant human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). Using xCELLigence real-time cell analyser (RTCA), we found that single high dose of ETP induces irreversible increase in hPSC-CMs beating rate and decrease in beating amplitude. We also identified 58 deregulated genes consisting of 33 upregulated and 25 downregulated genes in hPSC-CMs after ETP treatment. Gene ontology (GO) and pathway analysis showed that most upregulated genes are enriched in GO categories like positive regulation of apoptotic process, regulation of cell death, and mitochondria organization, whereas most downregulated genes were enriched in GO categories like cytoskeletal organization, muscle contraction, and Ca2+ ion homeostasis. Moreover, we also found upregulation in 5 miRNAs (has-miR-486-3p, has-miR-34c-5p, has-miR-4423-3p, has-miR-182-5p, and has-miR-139-5p) which play role in muscle contraction, arginine and proline metabolism, and hypertrophic cardiomyopathy (HCM). Immunostaining and transmission electron microscopy also confirmed the cytoskeletal and mitochondrial damage in hPSC-CMs treated with ETP, as well as noticeable alterations in intracellular calcium handling and mitochondrial membrane potential were also observed. The apoptosis inhibitor, Pifithrin-alpha, found to protect hPSC-CMs from ETP-induced cardiotoxicity, whereas hPSC-CMs treated with ferroptosis inhibitor, Liproxstatin-1, showed significant recovery in hPSC-CMs functional properties like beating rate and amplitude after ETP treatment. We suggest that the damage to mitochondria is a major contributing factor involved in ETP-induced cardiotoxicity and the activation of the p53-mediated ferroptosis pathway by ETP is likely the critical pathway in ETP-induced cardiotoxicity. We also conclude that the genomic biomarkers identified in this study will significantly contribute to develop and predict potential cardiotoxic effects of novel anti-cancer drugs in vitro.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Nemade, Harshal UNSPECIFIED UNSPECIFIED UNSPECIFIED Chaudhari, Umesh UNSPECIFIED orcid.org/0000-0002-7743-4371 UNSPECIFIED Acharya, Aviseka UNSPECIFIED UNSPECIFIED UNSPECIFIED Hescheler, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Hengstler, Jan Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Papadopoulos, Symeon UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-191492
DOI:	10.1007/s00204-018-2170-7
Journal or Publication Title:	Arch. Toxicol.
Volume:	92
Number:	4
Page Range:	S. 1507 - 1525
Date:	2018
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-0738
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GROWTH-DIFFERENTIATION FACTOR-15; HIGH-DOSE CYCLOPHOSPHAMIDE; NON-HODGKINS-LYMPHOMA; HEART-FAILURE; INDUCED APOPTOSIS; LUNG-CANCER; CARDIOVASCULAR-DISEASE; MITOCHONDRIAL FISSION; TESTICULAR CANCER; INDUCE APOPTOSIS Multiple languages Toxicology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19149