A comparative study on in vitro cytotoxicity, cellular uptake, localization and apoptosis-inducing mechanism of two ruthenium(II) complexes
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Two ruthenium complexes [Ru(MeIm)4(bpy)]2+ (Ru1, MeIm = 1-methylimidazole, bpy = 2,2′-bipyridine) and [Ru(Im)4(bpy)]2+ (Ru2, Im = imidazole) with the same PF 6 − counter-ion but different lipophilicities were synthesized and characterized and as potent anticancer agents. The relationships between cellular uptake, localization and molecular action mechanisms of these complexes were elucidated. The results showed that Ru1 with higher logPo/w exhibited faster cellular uptake rates, but lower anticancer activity than Ru2. In addition, Ru1 predominantly accumulated in the mitochondria and cytoplasm, and induced G0/G1 cell cycle arrest, whereas the more hydrophilic Ru2 tended to localize and accumulate in the cell nucleus and mitochondria. Further mechanism studies indicated that Ru2 caused cell cycle arrest at S phase by regulating cell cycle related proteins and induced apoptosis in A549 cells through DNA damage, cellular ROS accumulation, activation of the caspase pathway and mitochondrial dysfunction.
This work was supported by the National Natural Science Foundation of China (No. 21701034), Guangdong Provincial Bureau of traditional Chinese Medicine research foundation (No. 20161143), Training Plan of Guangdong Province Outstanding Young Teachers in Higher Education Institutions (No. YQ2015086), the Medical Scientific Research Foundation of Guangdong Province of China (No. A2016464, A2017309, A2016281), the Natural Science Foundation of Guangdong Medical University (No. Z2017001) and the University Student Innovation Experiment Program.
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