Apoptosis-independent organoruthenium anticancer complexes that overcome multidrug resistance: self-assembly and phenotypic screening strategies. Issue 5 (14th March 2017)

• Record Type: Journal Article
• Authors: Chow, Mun Juinn; Alfiean, Mohammad; Pastorin, Giorgia; Gaiddon, Christian; Ang, Wee Han
• Is Part Of: Chemical science. Volume 8:Issue 5(2017)
• Page Start: 3641
• Page End: 3649
• Publication Date: 2017-03-14
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c7sc00497d
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Phenotypic screening on a library of combinatorial self-assembled organoruthenium complexes revealed constructs that act on refractory cancers via apoptosis-independent pathways. Abstract : 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.