2. Academic Validation
  3. Disulfiram increases the efficacy of 5-fluorouracil in organotypic cultures of colorectal carcinoma

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

  • Biomed Pharmacother. 2022 Sep:153:113465. doi: 10.1016/j.biopha.2022.113465.
Michal Hendrych 1,  Kamila Říhová 2,  Barbora Adamová 3,  Vojtěch Hradil 3,  Marek Stiborek 4,  Petr Vlček 5,  Markéta Hermanová 1,  Jana Vašíčková 6,  Petr Beneš 2,  Jan Šmarda 3,  Viktor Kanický 4,  Jan Preisler 4,  Jarmila Navrátilová 7
Affiliations

Affiliations

  • 1 First Department of Pathology, St. Anne's University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
  • 2 Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital Brno, Czech Republic.
  • 3 Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
  • 4 Department of Chemistry, Faculty of Science, Masaryk University, Brno, Czech Republic.
  • 5 First Department of Surgery, St. Anne's University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
  • 6 International Clinical Research Center, St. Anne's University Hospital Brno, Czech Republic.
  • 7 Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital Brno, Czech Republic. Electronic address: [email protected].
PMID: 36076577 DOI: 10.1016/j.biopha.2022.113465
Abstract

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.

Keywords

5-fluorouracil; Colorectal carcinoma; Disulfiram/copper; Organotypic culture; Spheroid; Synergism.

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