| Autor: |
van Rixel VHS, Ramu V, Auyeung AB, Beztsinna N, Leger DY; Laboratoire PEIRENE EA7500, Faculté de Pharmacie , Université de Limoges , 2 rue du Dr Marcland , 87025 Limoges , France., Lameijer LN, Hilt ST, Le Dévédec SE, Yildiz T, Betancourt T, Gildner MB, Hudnall TW, Sol V; Laboratoire PEIRENE EA7500, Faculté de Pharmacie , Université de Limoges , 2 rue du Dr Marcland , 87025 Limoges , France., Liagre B; Laboratoire PEIRENE EA7500, Faculté de Pharmacie , Université de Limoges , 2 rue du Dr Marcland , 87025 Limoges , France., Kornienko A, Bonnet S |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of the American Chemical Society [J Am Chem Soc] 2019 Nov 20; Vol. 141 (46), pp. 18444-18454. Date of Electronic Publication: 2019 Nov 06. |
| DOI: |
10.1021/jacs.9b07225 |
| Abstrakt: |
Marine alkaloid rigidins are cytotoxic compounds known to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing a thioether group was "caged" by coordination of its thioether group to a photosensitive ruthenium complex. In the dark, the coordinated ruthenium fragment prevented the rigidin analogue from inhibiting tubulin polymerization and reduced its toxicity in 2D cancer cell line monolayers, 3D lung cancer tumor spheroids (A549), and a lung cancer tumor xenograft (A549) in nude mice. Photochemical activation of the prodrug upon green light irradiation led to the photosubstitution of the thioether ligand by water, thereby releasing the free rigidin analogue capable of inhibiting the polymerization of tubulin. In cancer cells, such photorelease was accompanied by a drastic reduction of cell growth, not only when the cells were grown in normoxia (21% O 2 ) but also remarkably in hypoxic conditions (1% O 2 ). In vivo , low toxicity was observed at a dose of 1 mg·kg -1 when the compound was injected intraperitoneally, and light activation of the compound in the tumor led to 30% tumor volume reduction, which represents the first demonstration of the safety and efficacy of ruthenium-based photoactivated chemotherapy compounds in a tumor xenograft. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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