Author:
Meßner Martina,Mandl Melanie M.,Hackl Mathias W.,Reinhardt Till,Ardelt Maximilian A.,Szczepanowska Karolina,Frädrich Julian E.,Waschke Jens,Jeremias Irmela,Fux Anja,Stahl Matthias,Vollmar Angelika M.,Sieber Stephan A.,Pachmayr Johanna
Abstract
AbstractThe 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.
Funder
Deutsche Forschungsgemeinschaft
Publisher
Springer Science and Business Media LLC
Cited by
2 articles.
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