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.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
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 Pdoi
10.1038/s41419-018-1102-zsubject
Has Abstractpub_date
2018-10-15 00:00:00pages
1052issue
11issn
2041-4889pii
10.1038/s41419-018-1102-zjournal_volume
9pub_type
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journal_title:Cell death & disease
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