Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
Journal article, 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.

Spheroid

VLX60

Thiosemicarbazone

BRAF

Cancer drug

Author

Henning Karlsson

Uppsala University

M. Fryknas

Uppsala University

Sara Strese

Uppsala University

J. Gullbo

Uppsala University

Gunnar Westman

Chalmers, Chemistry and Chemical Engineering, Chemistry and Biochemistry, Organic Chemistry

Ulf Bremberg

Uppsala University

Tobias Sjöblom

Uppsala University

Tatjana Pandzic

Uppsala University

R. Larsson

Uppsala University

Peter Nygren

Uppsala University

Oncotarget

1949-2553 (ISSN)

Vol. 8 18 30217-30234

Subject Categories

Cell Biology

DOI

10.18632/oncotarget.16324

PubMed

28415818

More information

Latest update

2/28/2018