The mycotoxin viriditoxin induces leukemia- and lymphoma-specific apoptosis by targeting mitochondrial metabolism.

Autor: Stuhldreier F; Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Schmitt L; Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Lenz T; Molecular Proteomics Laboratory, Biological-Medical-Research Center (BMFZ), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Hinxlage I; Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Zimmermann M; Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Wollnitzke P; Institute for Molecular Medicine III, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Schliehe-Diecks J; Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany., Liu Y; Institute of Pharmaceutical Biology and Biotechnology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Jäger P; Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany., Geyh S; Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany., Teusch N; Institute of Pharmaceutical Biology and Biotechnology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Peter C; Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Bhatia S; Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany., Haas R; Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany., Levkau B; Institute for Molecular Medicine III, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Reichert AS; Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Stühler K; Molecular Proteomics Laboratory, Biological-Medical-Research Center (BMFZ), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Proksch P; Institute of Pharmaceutical Biology and Biotechnology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Stork B; Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany., Wesselborg S; Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Düsseldorf, Germany. sebastian.wesselborg@uni-duesseldorf.de.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 Nov 08; Vol. 13 (11), pp. 938. Date of Electronic Publication: 2022 Nov 08.
DOI: 10.1038/s41419-022-05356-w
Abstrakt: Inhibition of the mitochondrial metabolism offers a promising therapeutic approach for the treatment of cancer. Here, we identify the mycotoxin viriditoxin (VDT), derived from the endophytic fungus Cladosporium cladosporioides, as an interesting candidate for leukemia and lymphoma treatment. VDT displayed a high cytotoxic potential and rapid kinetics of caspase activation in Jurkat leukemia and Ramos lymphoma cells in contrast to solid tumor cells that were affected to a much lesser extent. Most remarkably, human hematopoietic stem and progenitor cells and peripheral blood mononuclear cells derived from healthy donors were profoundly resilient to VDT-induced cytotoxicity. Likewise, the colony-forming capacity was affected only at very high concentrations, which provides a therapeutic window for cancer treatment. Intriguingly, VDT could directly activate the mitochondrial apoptosis pathway in leukemia cells in the presence of antiapoptotic Bcl-2 proteins. The mitochondrial toxicity of VDT was further confirmed by inhibition of mitochondrial respiration, breakdown of the mitochondrial membrane potential (ΔΨm), the release of mitochondrial cytochrome c, generation of reactive oxygen species (ROS), processing of the dynamin-like GTPase OPA1 and subsequent fission of mitochondria. Thus, VDT-mediated targeting of mitochondrial oxidative phosphorylation (OXPHOS) might represent a promising therapeutic approach for the treatment of leukemia and lymphoma without affecting hematopoietic stem and progenitor cells.
(© 2022. The Author(s).)
Databáze: MEDLINE
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