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Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity

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 M...

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Autores principales: Karlsson, Henning, Fryknäs, Mårten, Strese, Sara, Gullbo, Joachim, Westman, Gunnar, Bremberg, Ulf, Sjöblom, Tobias, Pandzic, Tatjana, Larsson, Rolf, Nygren, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444738/
https://www.ncbi.nlm.nih.gov/pubmed/28415818
http://dx.doi.org/10.18632/oncotarget.16324
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author Karlsson, Henning
Fryknäs, Mårten
Strese, Sara
Gullbo, Joachim
Westman, Gunnar
Bremberg, Ulf
Sjöblom, Tobias
Pandzic, Tatjana
Larsson, Rolf
Nygren, Peter
author_facet Karlsson, Henning
Fryknäs, Mårten
Strese, Sara
Gullbo, Joachim
Westman, Gunnar
Bremberg, Ulf
Sjöblom, Tobias
Pandzic, Tatjana
Larsson, Rolf
Nygren, Peter
author_sort Karlsson, Henning
collection PubMed
description 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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spelling pubmed-54447382017-06-01 Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity Karlsson, Henning Fryknäs, Mårten Strese, Sara Gullbo, Joachim Westman, Gunnar Bremberg, Ulf Sjöblom, Tobias Pandzic, Tatjana Larsson, Rolf Nygren, Peter Oncotarget Research Paper 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. Impact Journals LLC 2017-03-17 /pmc/articles/PMC5444738/ /pubmed/28415818 http://dx.doi.org/10.18632/oncotarget.16324 Text en Copyright: © 2017 Karlsson et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Karlsson, Henning
Fryknäs, Mårten
Strese, Sara
Gullbo, Joachim
Westman, Gunnar
Bremberg, Ulf
Sjöblom, Tobias
Pandzic, Tatjana
Larsson, Rolf
Nygren, Peter
Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
title Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
title_full Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
title_fullStr Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
title_full_unstemmed Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
title_short Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
title_sort mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444738/
https://www.ncbi.nlm.nih.gov/pubmed/28415818
http://dx.doi.org/10.18632/oncotarget.16324
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