Apoptosis-independent organoruthenium anticancer complexes that overcome multidrug resistance: self-assembly and phenotypic screening strategies

Chemical Science
Mun Juinn ChowWee Han Ang

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.

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Citations

Mar 15, 2019·Chemical Communications : Chem Comm·Leli ZengHui Chao
May 18, 2020·Chembiochem : a European Journal of Chemical Biology·Arvin EskandariKogularamanan Suntharalingam
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May 31, 2017·Chemistry : a European Journal·Marie FlammeKogularamanan Suntharalingam
May 26, 2021·Dalton Transactions : an International Journal of Inorganic Chemistry·Priyaranjan KumarAshis K Patra
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Apr 17, 2019·ACS Applied Materials & Interfaces·Shan-Wen HuJing-Juan Xu
Apr 25, 2020·Journal of Inorganic Biochemistry·Jorge Andrés Solís-RuizRonan Le Lagadec

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Methods Mentioned

BETA
silica gel column chromatography

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