Structural Determinants of p53-Independence in Anticancer Ruthenium-Arene Schiff-Base Complexes.
Fiche publication
Date publication
juillet 2016
Journal
Molecular pharmaceutics
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GAIDDON Christian
Tous les auteurs :
Chow MJ, Babak MV, Wong DY, Pastorin G, Gaiddon C, Ang WH
Lien Pubmed
Résumé
p53 is a key tumor suppressor gene involved in key cellular processes and implicated in cancer therapy. However, it is inactivated in more than 50% of all cancers due to mutation or overexpression of its negative regulators. This leads to drug resistance and poor chemotherapeutic outcome as most clinical drugs act via a p53-dependent mechanism of action. An attractive strategy to circumvent this resistance would be to identify new anticancer drugs that act via p53-independent mode of action. In the present study, we identified 9 Ru (II)-Arene Schiff-base (RAS) complexes able to induce p53-independent cytotoxicity and discuss structural features that are required for their p53-independent activity. Increasing hydrophobicity led to an increase in cellular accumulation in cells with a corresponding increase in efficacy. We further showed that all nine complexes demonstrated p53-independent activity. This was despite significant differences in their physicochemical properties, suggesting that the iminoquinoline ligand, a common structural feature for all the complexes, is required for the p53-independent activity.
Référence
Mol. Pharm.. 2016 Jul;13(7):2543-54