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Article Dans Une Revue Nucleic Acids Research Année : 2023

A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression

Marco Deiana
José María Andrés Castán
Pierre Josse
Abraha Kahsay
  • Fonction : Auteur
Korentin Morice
  • Fonction : Auteur
Natacha Gillet
Pallabi Sengupta
Ikenna Obi
Eva Rodriguez-Marquez
  • Fonction : Auteur
Lhoussain Khrouz
Elise Dumont
Laura Abad Galán
Magali Allain
Bright Walker
Hyun Seo Ahn
Olivier Maury
Philippe Blanchard
Daniel Öhlund
Jonas von Hofsten
Cyrille Monnereau
Nasim Sabouri

Résumé

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.
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Origine : Publication financée par une institution

Dates et versions

hal-04247125 , version 1 (18-10-2023)

Identifiants

Citer

Marco Deiana, José María Andrés Castán, Pierre Josse, Abraha Kahsay, Darío Puchán Sánchez, et al.. A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression. Nucleic Acids Research, 2023, 51 (12), pp.6264-6285. ⟨10.1093/nar/gkad365⟩. ⟨hal-04247125⟩
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