Structural tuning of organoruthenium compounds allows oxidative switch to control ER stress pathways and bypass multidrug resistance.
Fiche publication
Date publication
juillet 2016
Journal
Chemical science
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GAIDDON Christian, Dr MELLITZER Georg
Tous les auteurs :
Chow MJ, Licona C, Pastorin G, Mellitzer G, Ang WH, Gaiddon C
Lien Pubmed
Résumé
Multidrug resistance (MDR) is a major impediment to the success of chemotherapy in many cancer types. One particular MDR mechanism is the inherent or acquired adaptation of the cellular survival pathways that render malignant cells resistant to apoptotic cell death. Since most drugs act through apoptosis, compounds capable of inducing alternative forms of programmed cell death (PCD) can potentially be harnessed to bypass MDR. We investigated two organoruthenium complexes, RAS-1H and RAS-1T, and demonstrated that although they both induced non-apoptotic PCD through ER stress pathways, their modes-of-action were drastically different despite modest structural variations. RAS-1T acted through ROS-mediated ER stress while RAS-1H was ROS-independent. We further showed that they were more efficacious against apoptosis-resistant cells compared to clinical drugs including oxaliplatin. This work provides the basis for underpinning ER stress modulation using metal complexes to bypass apoptosis resistance.
Référence
Chem Sci. 2016 Jul 1;7(7):4117-4124