Oncotarget

Research Papers:

Diphenyl ditelluride anticancer activity and DNA topoisomerase I poisoning in human colon cancer HCT116 cells

André Luiz Mendes Juchem, Cristiano Trindade, Juliana Bondan da Silva, Miriana da Silva Machado, Temenouga Nikolova Guecheva, Jaqueline Cesar Rocha, Jenifer Saffi, Iuri Marques de Oliveira, João Antonio Pêgas Henriques _ and Alexandre Escargueil _

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Oncotarget. 2023; 14:637-649. https://doi.org/10.18632/oncotarget.28465

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Abstract

André Luiz Mendes Juchem1,2,*, Cristiano Trindade3,*, Juliana Bondan da Silva4, Miriana da Silva Machado1, Temenouga Nikolova Guecheva1,5, Jaqueline Cesar Rocha3, Jenifer Saffi3, Iuri Marques de Oliveira1, João Antonio Pêgas Henriques1,6 and Alexandre Escargueil2

1 Department of Biophysics/Postgraduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

2 Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris F-75012, France

3 Department of Basic Health Sciences, Federal University of Health Sciences of Porto Alegre – UFCSPA, Porto Alegre - RS, Brazil

4 Department of Postgraduate Program in Molecular and Cell Biology Applied to Health, Lutheran University of Brazil (ULBRA), Canoas, Brazil

5 Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria

6 Postgraduate Program in Biotechnology and Medical Sciences, University of Vale do Taquari - UNIVATES, Lajeado - RS, Brazil

* These authors contributed equally to this work

Correspondence to:

João Antonio Pêgas Henriques, email: [email protected]
Alexandre Escargueil, email: [email protected]

Keywords: colorectal cancer; HCT116; diphenyl ditelluride; organotellurium; topoisomerase I

Received: May 02, 2023     Accepted: June 02, 2023     Published: June 21, 2023

Copyright: © 2023 Juchem et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Diphenyl ditelluride (DPDT) is an organotellurium (OT) compound with pharmacological properties, including antioxidant, antigenotoxic and antimutagenic activities when applied at low concentrations. However, DPDT as well as other OT compounds also show cytotoxicity against mammalian cells when treatments occur at higher drug concentrations. Considering that the underlying mechanisms of toxicity of DPDT against tumor cells have been poorly explored, the objective of our study was to investigate the effects of DPDT against both human cancer and non-tumorigenic cells. As a model, we used the colonic HCT116 cancer cells and the MRC5 fibroblasts. Our results showed that DPDT preferentially targets HCT116 cancer cells when compared to MRC5 cells with IC50 values of 2.4 and 10.1 μM, respectively. This effect was accompanied by the induction of apoptosis and a pronounced G2/M cell cycle arrest in HCT116 cells. Furthermore, DPDT induces DNA strand breaks at concentrations below 5 μM in HCT116 cells and promotes the occurrence of DNA double strand breaks mostly during S-phase as measured by γ-H2AX/EdU double staining. Finally, DPDT forms covalent complexes with DNA topoisomerase I, as observed by the TARDIS assay, with a more prominent effect observed in HCT116 than in MRC5 cells. Taken together, our results show that DPDT preferentially targets HCT116 colon cancer cells likely through DNA topoisomerase I poisoning. This makes DPDT an interesting molecule for further development as an anti-proliferative compound in the context of cancer.


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