Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers

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 be...

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Autores principales:	Martina Meßner, Melanie M. Mandl, Mathias W. Hackl, Till Reinhardt, Maximilian A. Ardelt, Karolina Szczepanowska, Julian E. Frädrich, Jens Waschke, Irmela Jeremias, Anja Fux, Matthias Stahl, Angelika M. Vollmar, Stephan A. Sieber, Johanna Pachmayr
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/547435541d554b50bc1ec5f3fc98a476
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spelling	oai:doaj.org-article:547435541d554b50bc1ec5f3fc98a4762021-12-02T14:47:38ZSmall molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers10.1038/s41598-021-90801-72045-2322https://doaj.org/article/547435541d554b50bc1ec5f3fc98a4762021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90801-7https://doaj.org/toc/2045-2322Abstract 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.Martina MeßnerMelanie M. MandlMathias W. HacklTill ReinhardtMaximilian A. ArdeltKarolina SzczepanowskaJulian E. FrädrichJens WaschkeIrmela JeremiasAnja FuxMatthias StahlAngelika M. VollmarStephan A. SieberJohanna PachmayrNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Martina Meßner Melanie M. Mandl Mathias W. Hackl Till Reinhardt Maximilian A. Ardelt Karolina Szczepanowska Julian E. Frädrich Jens Waschke Irmela Jeremias Anja Fux Matthias Stahl Angelika M. Vollmar Stephan A. Sieber Johanna Pachmayr Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers
description	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.
format	article
author	Martina Meßner Melanie M. Mandl Mathias W. Hackl Till Reinhardt Maximilian A. Ardelt Karolina Szczepanowska Julian E. Frädrich Jens Waschke Irmela Jeremias Anja Fux Matthias Stahl Angelika M. Vollmar Stephan A. Sieber Johanna Pachmayr
author_facet	Martina Meßner Melanie M. Mandl Mathias W. Hackl Till Reinhardt Maximilian A. Ardelt Karolina Szczepanowska Julian E. Frädrich Jens Waschke Irmela Jeremias Anja Fux Matthias Stahl Angelika M. Vollmar Stephan A. Sieber Johanna Pachmayr
author_sort	Martina Meßner
title	Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers
title_short	Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers
title_full	Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers
title_fullStr	Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers
title_full_unstemmed	Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers
title_sort	small molecule inhibitors of the mitochondrial clpxp protease possess cytostatic potential and re-sensitize chemo-resistant cancers
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/547435541d554b50bc1ec5f3fc98a476
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Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers

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