DNA templated Click Chemistry via 5-vinyl-2′-deoxyuridine and an acridine-tetrazine conjugate induces DNA damage and apoptosis in cancer cells

Click Chemistry is providing valuable tools to biomedical research, but its direct use in therapies remains nearly unexplored. For cancer treatment, nucleoside analogues (NA) such as 5-vinyl-2′-deoxyuridine (VdU) can be metabolically incorporated into cancer cell DNA and subsequently “clicked” to fo...

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Bibliographic Details
Published in:	Life sciences (1973) Vol. 330; p. 122000
Main Authors:	Li, Yizhu, Ling, Yurong, Loehr, Morten O., Chaabane, Sabrina, Cheng, Oh Wan, Zhao, Kaifeng, Wu, Chao, Büscher, Moritz, Weber, Jana, Stomakhine, Daria, Munker, Marina, Pientka, Ronja, Christ, Sarah B., Dobbelstein, Matthias, Luedtke, Nathan W.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Inc 01-10-2023
Subjects:	cancer Chemotherapy Click Chemistry DNA damage Nucleoside analogues Chemotherapy cancer Click Chemistry Nucleoside analogues DNA damage
Online Access:	Get full text
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Summary:	Click Chemistry is providing valuable tools to biomedical research, but its direct use in therapies remains nearly unexplored. For cancer treatment, nucleoside analogues (NA) such as 5-vinyl-2′-deoxyuridine (VdU) can be metabolically incorporated into cancer cell DNA and subsequently “clicked” to form a toxic product. The inverse electron-demand Diels-Alder (IEDDA) reaction between VdU and an acridine-tetrazine conjugate (PINK) has previously been used to label cell nuclei of cultured cells. Here, we report tandem usage of VdU and PINK to induce cytotoxicity. Cell lines were subsequently treated with VdU and PINK, and cell viability was measured via well confluency and 3D tumor spheroid assays. DNA damage and apoptosis were evaluated using Western Blotting and cell cycle analysis by flow cytometry. Double stranded DNA break (DSB) formation was measured using the comet assay. Apoptosis was assessed by fluorescent detection of externalized phosphatidylserine residues. We report that the combination of VdU and PINK synergistically induces cytotoxicity in cultured human cells. The combination of VdU and PINK strongly reduced cell viability in 2D and 3D cultured cancer cells. Mechanistically, the compounds induced DNA damage through DSB formation, which leads to S-phase accumulation and apoptosis. The combination of VdU and PINK represents a novel and promising DNA-templated “click” approach for cancer treatment via selective induction of DNA damage. [Display omitted] •NA templated tetrazine ligation reduces viability of human cultured cells.•VdU and PINK strongly inhibit cell proliferation in adherent and 3D cultured cells.•The combination induces DNA damage and cell cycle alterations.•VdU and PINK induce DNA damage via DSB formation in the comet assay.•Click Chemistry induced DNA damage leads to apoptosis in human cultured cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0024-3205 1879-0631
DOI:	10.1016/j.lfs.2023.122000