Disulfiram increases the efficacy of 5-fluorouracil in organotypic cultures of colorectal carcinoma

Drug efficacy determined in preclinical research is difficult to transfer to clinical practice. This is mainly due to the use of oversimplified models omitting the effect of the tumor microenvironment and the presence of various cell types participating in the formation of tumors in vivo. In this st...

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Bibliographic Details
Published in:Biomedicine & pharmacotherapy 2022-09, Vol.153, p.113465-113465, Article 113465
Main Authors: Hendrych, Michal, Říhová, Kamila, Adamová, Barbora, Hradil, Vojtěch, Stiborek, Marek, Vlček, Petr, Hermanová, Markéta, Vašíčková, Jana, Beneš, Petr, Šmarda, Jan, Kanický, Viktor, Preisler, Jan, Navrátilová, Jarmila
Format: Article
Language:English
Subjects:
5-fluorouracil
Colorectal carcinoma
Disulfiram/copper
Organotypic culture
Spheroid
Synergism
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Summary:Drug efficacy determined in preclinical research is difficult to transfer to clinical practice. This is mainly due to the use of oversimplified models omitting the effect of the tumor microenvironment and the presence of various cell types participating in the formation of tumors in vivo. In this study, we used robust three-dimensional models including spheroids grown from colon cancer cell lines and organotypic cultures prepared from the colorectal carcinoma tissue to test novel therapeutic strategies. We developed a multi-modal approach combining brightfield and fluorescence microscopy for evaluating drug effects on organotypic cultures. Combined treatment with 5-fluorouracil and disulfiram/copper efficiently eliminated cancer cells in these 3D models. Moreover, disulfiram/copper down-regulated the expression of markers associated with 5-fluorouracil resistance, such as thymidylate synthase and CD133/CD44. Thus, we propose combined therapy of 5-fluorouracil and disulfiram/copper for further testing as a treatment for colorectal carcinoma. In addition, we show that organotypic cultures are suitable models for anti-cancer drug testing. [Display omitted] •Spheroids grown from colon cancer cell lines and colon cancer organotypic cultures.•Semiautomated data processing for drug testing in three-dimensional models.•Disulfiram/copper complex promotes 5-fluorouracil antitumor effect on colon cancer.•Disulfiram/copper reduces the expression of 5-fluorouracil resistance markers.•Personalized approach to therapy testing due to the variability in tumor response.
ISSN:0753-3322
1950-6007
DOI:10.1016/j.biopha.2022.113465