Abstract
Ruthenium-based complexes have been regarded as one of the most potential metal-based candidates for anticancer therapy. Herein, two ruthenium (II) methylimidazole complexes [Ru(MeIm)4(4npip)]2+ (complex 1) and [Ru(MeIm)4(4mopip)]2+ (complex 2) were synthesized and evaluated for their in vitro anticancer activities. The results showed that these ruthenium (II) methylimidazole complexes exhibited moderate antitumor activity comparable with cisplatin against A549, NCI-H460, MCF-7 and HepG2 human cancer cells, but with less toxicity to a human normal cell line HBE. Intracellular distribution studies suggested that complex 2 selectively localized in the mitochondria. Mechanism studies indicated that complex 2 caused cell cycle arrest at G0/G1 phase by regulating cell cycle relative proteins and induced apoptosis through intrinsic pathway, which involved mitochondrial dysfunction, reactive oxygen species (ROS) accumulation and ROS-mediated DNA damage. Further, studies by western blotting suggested that MAPK and AKT signaling pathways were involved in complex 2-induced apoptosis, and they were regulated by the level of ROS. Overall, these findings suggested that complex 2 could be a candidate for further evaluation as a chemotherapeutic agent in the treatment of cancers.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (21701034), Guangdong Provincial Bureau of traditional Chinese Medicine research foundation (No. 20161143), Training Plan of Guangdong Province Outstanding Young Teachers in Higher Education Institutions (Nos. YQ201401, YQ2015086), the Medical Scientific Research Foundation of Guangdong Province of China (Nos. A2015500, A2016464, A2017309), and the University Student Innovation Experiment Program (Nos. 201710571004, 201710571017, 201610571062).
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Chen, J., Zhang, Y., Li, G. et al. Cytotoxicity in vitro, cellular uptake, localization and apoptotic mechanism studies induced by ruthenium(II) complex. J Biol Inorg Chem 23, 261–275 (2018). https://doi.org/10.1007/s00775-017-1528-2
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DOI: https://doi.org/10.1007/s00775-017-1528-2