Apoptosis-independent organoruthenium anticancer complexes that overcome multidrug resistance: self-assembly and phenotypic screening strategies.
Fiche publication
Date publication
mai 2017
Journal
Chemical science
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GAIDDON Christian
Tous les auteurs :
Chow MJ, Alfiean M, Pastorin G, Gaiddon C, Ang WH
Lien Pubmed
Résumé
Multidrug resistance is a major impediment to chemotherapy and limits the efficacies of conventional anticancer drugs. A strategy to bypass multidrug resistance is to develop new drug candidates capable of inducing apoptosis-independent programmed cell death. However, cellular pathways implicated in alternative programmed cell death are not well-elucidated and multifactorial, making a target-based discovery approach a challenge. Here, we show that a coordination-directed three-component assembly and phenotypic screening strategy could be employed as a viable alternative for the identification of apoptosis-independent organoruthenium anticancer agents. Through an on-plate synthesis and screening of 195 organoruthenium complexes against apoptosis-sensitive and -resistant cancers, we identified two apoptosis-independent hits. Subsequent validation of the two hits showed a lack of induction of apoptotic biomarkers, a caspase-independent activity and an equal efficacy in both apoptosis-sensitive and -resistant colorectal cancers. This validated their apoptosis-independent modes-of-action, paving the way as potential candidates for the treatment of highly-refractory cancer phenotypes.
Référence
Chem Sci. 2017 May 1;8(5):3641-3649