2. Academic Validation
  3. Novel meriolin derivatives activate the mitochondrial apoptosis pathway in the presence of antiapoptotic Bcl-2

Novel meriolin derivatives activate the mitochondrial apoptosis pathway in the presence of antiapoptotic Bcl-2

  • Cell Death Discov. 2024 Mar 9;10(1):125. doi: 10.1038/s41420-024-01901-y.
Laura Schmitt # 1,  Ilka Lechtenberg # 1,  Daniel Drießen 2,  Hector Flores-Romero 3 4 5 6,  Margaretha A Skowron 7,  Marlena Sekeres 8,  Julia Hoppe 1,  Karina S Krings 1,  Tanya R Llewellyn 9,  Christoph Peter 1,  Björn Stork 1,  Nan Qin 9,  Sanil Bhatia 10,  Daniel Nettersheim 7,  Gerhard Fritz 8,  Ana J García-Sáez 3 4,  Thomas J J Müller 2,  Sebastian Wesselborg 11
Affiliations

Affiliations

  • 1 Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.
  • 2 Institute of Organic Chemistry and Macromolecular Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.
  • 3 Institute for Genetics, Faculty of Mathematics and Natural Sciences, University of Cologne, 50931, Cologne, Germany.
  • 4 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany.
  • 5 Ikerbasque, Basque Foundation for Science, 48013, Bilbao, Spain.
  • 6 Achucarro Basque Center for Neuroscience, Leioa, Spain.
  • 7 Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, Düsseldorf, Germany.
  • 8 Institute of Toxicology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.
  • 9 Clinic of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.
  • 10 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.
  • 11 Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany. [email protected].
  • # Contributed equally.
PMID: 38461295 DOI: 10.1038/s41420-024-01901-y
Abstract

Meriolin derivatives represent a new class of kinase inhibitors with a pronounced cytotoxic potential. Here, we investigated a newly synthesized meriolin derivative (termed meriolin 16) that displayed a strong apoptotic potential in Jurkat leukemia and Ramos lymphoma cells. Meriolin 16 induced Apoptosis in rapid kinetics (within 2-3 h) and more potently (IC50: 50 nM) than the previously described derivatives meriolin 31 and 36 [1]. Exposure of Ramos cells to meriolin 16, 31, or 36 for 5 min was sufficient to trigger severe and irreversible cytotoxicity. Apoptosis induction by all three meriolin derivatives was independent of death receptor signaling but required caspase-9 and Apaf-1 as central mediators of the mitochondrial death pathway. Meriolin-induced mitochondrial toxicity was demonstrated by disruption of the mitochondrial membrane potential (ΔΨm), mitochondrial release of proapoptotic Smac, processing of the dynamin-like GTPase OPA1, and subsequent fragmentation of mitochondria. Remarkably, all meriolin derivatives were able to activate the mitochondrial death pathway in Jurkat cells, even in the presence of the antiapoptotic Bcl-2 protein. In addition, meriolins were capable of inducing cell death in imatinib-resistant K562 and KCL22 chronic myeloid leukemia cells as well as in cisplatin-resistant J82 urothelial carcinoma and 2102EP germ cell tumor cells. Given the frequent inactivation of the mitochondrial Apoptosis pathway by tumor cells, such as through overexpression of antiapoptotic Bcl-2, meriolin derivatives emerge as promising therapeutic agents for overcoming treatment resistance.

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