The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition

Sonja Hager, Katharina Korbula, Björn Bielec, Michael Grusch, Christine Pirker, Markus Schosserer, Lisa Liendl, Magdalena Lang, Johannes Grillari, Karin Nowikovsky, Veronika F.S. Pape, Thomas Mohr, G. Szakács, Bernhard K. Keppler, Walter Berger, Christian R. Kowol, Petra Heffeter

Research output: Contribution to journalArticle

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Abstract

Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest based on their enhanced cytotoxic activity. Increasing evidence suggests that the double-dimethylated Triapine derivative Me2NNMe2 differs from Triapine not only in its efficacy but also in its mode of action. Here we show that Me2NNMe2- (but not Triapine)-treated cancer cells exhibit all hallmarks of paraptotic cell death including, besides the appearance of endoplasmic reticulum (ER)-derived vesicles, also mitochondrial swelling and caspase-independent cell death via the MAPK signaling pathway. Subsequently, we uncover that the copper complex of Me2NNMe2 (a supposed intracellular metabolite) inhibits the ER-resident protein disulfide isomerase, resulting in a specific form of ER stress based on disruption of the Ca2+ and ER thiol redox homeostasis. Our findings indicate that compounds like Me2NNMe2 are of interest especially for the treatment of apoptosis-resistant cancer and provide new insights into mechanisms underlying drug-induced paraptosis.

Original languageEnglish
Article number1052
JournalCell Death and Disease
Volume9
Issue number11
DOIs
Publication statusPublished - Nov 1 2018

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Thiosemicarbazones
Protein Disulfide-Isomerases
Sulfhydryl Compounds
Endoplasmic Reticulum
Oxidation-Reduction
Homeostasis
Cell Death
Mitochondrial Swelling
Neoplasms
Endoplasmic Reticulum Stress
Caspases
Copper
Clinical Trials
Apoptosis
3-aminopyridine-2-carboxaldehyde thiosemicarbazone
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition. / Hager, Sonja; Korbula, Katharina; Bielec, Björn; Grusch, Michael; Pirker, Christine; Schosserer, Markus; Liendl, Lisa; Lang, Magdalena; Grillari, Johannes; Nowikovsky, Karin; Pape, Veronika F.S.; Mohr, Thomas; Szakács, G.; Keppler, Bernhard K.; Berger, Walter; Kowol, Christian R.; Heffeter, Petra.

In: Cell Death and Disease, Vol. 9, No. 11, 1052, 01.11.2018.

Research output: Contribution to journalArticle

Hager, S, Korbula, K, Bielec, B, Grusch, M, Pirker, C, Schosserer, M, Liendl, L, Lang, M, Grillari, J, Nowikovsky, K, Pape, VFS, Mohr, T, Szakács, G, Keppler, BK, Berger, W, Kowol, CR & Heffeter, P 2018, 'The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition', Cell Death and Disease, vol. 9, no. 11, 1052. https://doi.org/10.1038/s41419-018-1102-z
Hager, Sonja ; Korbula, Katharina ; Bielec, Björn ; Grusch, Michael ; Pirker, Christine ; Schosserer, Markus ; Liendl, Lisa ; Lang, Magdalena ; Grillari, Johannes ; Nowikovsky, Karin ; Pape, Veronika F.S. ; Mohr, Thomas ; Szakács, G. ; Keppler, Bernhard K. ; Berger, Walter ; Kowol, Christian R. ; Heffeter, Petra. / The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition. In: Cell Death and Disease. 2018 ; Vol. 9, No. 11.
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