A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression
| Autor: | Marco Deiana, José María Andrés Castán, Pierre Josse, Abraha Kahsay, Darío Puchán Sánchez, Korentin Morice, Natacha Gillet, Ranjitha Ravindranath, Ankit Kumar Patel, Pallabi Sengupta, Ikenna Obi, Eva Rodriguez-Marquez, Lhoussain Khrouz, Elise Dumont, Laura Abad Galán, Magali Allain, Bright Walker, Hyun Seo Ahn, Olivier Maury, Philippe Blanchard, Tangui Le Bahers, Daniel Öhlund, Jonas von Hofsten, Cyrille Monnereau, Clément Cabanetos, Nasim Sabouri |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Nucleic Acids Research. |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | Photodynamic therapy (PDT) ideally relies on the administration, selective accumulation and photoactivation of a photosensitizer (PS) into diseased tissues. In this context, we report a new heavy-atom-free fluorescent G-quadruplex (G4) DNA-binding PS, named DBI. We reveal by fluorescence microscopy that DBI preferentially localizes in intraluminal vesicles (ILVs), precursors of exosomes, which are key components of cancer cell proliferation. Moreover, purified exosomal DNA was recognized by a G4-specific antibody, thus highlighting the presence of such G4-forming sequences in the vesicles. Despite the absence of fluorescence signal from DBI in nuclei, light-irradiated DBI-treated cells generated reactive oxygen species (ROS), triggering a 3-fold increase of nuclear G4 foci, slowing fork progression and elevated levels of both DNA base damage, 8-oxoguanine, and double-stranded DNA breaks. Consequently, DBI was found to exert significant phototoxic effects (at nanomolar scale) toward cancer cell lines and tumor organoids. Furthermore, in vivo testing reveals that photoactivation of DBI induces not only G4 formation and DNA damage but also apoptosis in zebrafish, specifically in the area where DBI had accumulated. Collectively, this approach shows significant promise for image-guided PDT. |
| Databáze: | OpenAIRE |
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