Targeting Mitochondrial Guanine Quadruplexes for Photoactivatable Chemotherapy in Hypoxic Environments.

Autor: Holden L; School of Chemical Sciences National Center for Sensor Research, Dublin City University, Dublin, 9, Ireland., Curley RC; School of Chemical Sciences National Center for Sensor Research, Dublin City University, Dublin, 9, Ireland., Avella G; School of Chemical Sciences National Center for Sensor Research, Dublin City University, Dublin, 9, Ireland., Long C; School of Chemical Sciences National Center for Sensor Research, Dublin City University, Dublin, 9, Ireland., Keyes TE; School of Chemical Sciences National Center for Sensor Research, Dublin City University, Dublin, 9, Ireland.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Oct 07; Vol. 63 (41), pp. e202408581. Date of Electronic Publication: 2024 Sep 05.
DOI: 10.1002/anie.202408581
Abstrakt: A first example of a mitochondrial G-quadruplex (mitoG4s) targeted Ru(II) photooxidant complex is reported. The complex, Ru-TAP-PDC3 induces photodamage toward guanine quadruplexes (G4s) located in the mitochondrial genome under hypoxic and normoxic conditions. Ru-TAP-PDC3 shows high affinity for mitoG4s and localises within mitochondria of live HeLa cells. Immunolabelling with anti-G4 antibody, BG4, confirms Ru-TAP-PDC3 associates with G4s within the mitochondria of fixed cells. The complex induces depletion of mtDNA in live cells under irradiation at 405 nm, confirmed by loss of PicoGreen signal from mitochondria. Biochemical studies confirm this process induces apoptosis. The complex shows low dark toxicity and an impressive phototoxicity index (PI) of >89 was determined in Hela under very low intensity irradiation, 5 J/cm 2 . The phototoxicity is thought to operate through both Type II singlet oxygen and Type III pathways depending on normoxic or hypoxic conditions, from live cell assays and plasmid DNA cleavage. Overall, we demonstrate targeting mitoG4s and mtDNA with a photooxidant is a potent route to achieving apoptosis under hypoxic conditions that can be extended to phototherapy.
(© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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