Universität zu Köln

Messner, Martina, Mandl, Melanie M., Hackl, Mathias W., Reinhardt, Till, Ardelt, Maximilian A., Szczepanowska, Karolina ORCID: 0000-0003-4689-2350, Fraedrich, Julian E., Waschke, Jens, Jeremias, Irmela ORCID: 0000-0003-1773-7677, Fux, Anja, Stahl, Matthias, Vollmar, Angelika M., Sieber, Stephan A. and Pachmayr, Johanna (2021). Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers. Sci Rep, 11 (1). BERLIN: NATURE RESEARCH. ISSN 2045-2322

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Abstract

The human mitochondrial ClpXP protease complex (HsClpXP) has recently attracted major attention as a target for novel anti-cancer therapies. Despite its important role in disease progression, the cellular role of HsClpXP is poorly characterized and only few small molecule inhibitors have been reported. Herein, we screened previously established S. aureus ClpXP inhibitors against the related human protease complex and identified potent small molecules against human ClpXP. The hit compounds showed anti-cancer activity in a panoply of leukemia, liver and breast cancer cell lines. We found that the bacterial ClpXP inhibitor 334 impairs the electron transport chain (ETC), enhances the production of mitochondrial reactive oxygen species (mtROS) and thereby promotes protein carbonylation, aberrant proteostasis and apoptosis. In addition, 334 induces cell death in re-isolated patient-derived xenograft (PDX) leukemia cells, potentiates the effect of DNA-damaging cytostatics and re-sensitizes resistant cancers to chemotherapy in non-apoptotic doses.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Messner, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Mandl, Melanie M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hackl, Mathias W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, Till UNSPECIFIED UNSPECIFIED UNSPECIFIED Ardelt, Maximilian A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Szczepanowska, Karolina UNSPECIFIED orcid.org/0000-0003-4689-2350 UNSPECIFIED Fraedrich, Julian E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Waschke, Jens UNSPECIFIED UNSPECIFIED UNSPECIFIED Jeremias, Irmela UNSPECIFIED orcid.org/0000-0003-1773-7677 UNSPECIFIED Fux, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED Stahl, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Vollmar, Angelika M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sieber, Stephan A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pachmayr, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-596510
DOI:	10.1038/s41598-021-90801-7
Journal or Publication Title:	Sci Rep
Volume:	11
Number:	1
Date:	2021
Publisher:	NATURE RESEARCH
Place of Publication:	BERLIN
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MULTIDRUG-RESISTANCE; INDUCED APOPTOSIS; DRUG-RESISTANCE; STRESS; ROLES; CELLS; CIPP; CARBONYLATION; DYSFUNCTION; MECHANISMS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59651