Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
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Henning Karlsson1, Mårten Fryknäs1, Sara Strese1, Joachim Gullbo1,2, Gunnar Westman3, Ulf Bremberg4, Tobias Sjöblom2, Tatjana Pandzic2, Rolf Larsson1, Peter Nygren2
1Department of Medical Sciences, Uppsala University, Uppsala, Sweden
2Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
3Department of Chemistry and Chemical Engineering, Chalmers University of Technology, Gothenburg, Sweden
4Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
Henning Karlsson, email: [email protected]
Keywords: cancer drug, thiosemicarbazone, spheroid, VLX60, BRAF
Received: September 07, 2016 Accepted: March 08, 2017 Published: March 17, 2017
Background: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties.
Materials and Methods: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50.
Results: VLX60 showed ≥ 3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells.
Conclusions: The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.
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