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A comparative study on in vitro cytotoxicity, cellular uptake, localization and apoptosis-inducing mechanism of two ruthenium(II) complexes

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Abstract

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.

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Acknowledgements

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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    Authors and Affiliations

    1. Analysis Centre of Guangdong Medical University, Zhanjiang, 524023, China

      Jincan Chen & Xinming Jie

    2. Guangdong Key Laboratory for Research and Development of Nature Drugs, Guangdong Medical University, Zhanjiang, 524023, China

      Jincan Chen

    3. Dongguan Key Laboratory of Drug Design and Formulation Technology, School of Pharmacy, Guangdong Medical University, Dongguan, 523808, China

      Yao Zhang, Baojun Li, Guodong Li, Zhilin Zou, Xiaofeng Huang, Jiaoyue Qu & Lanmei Chen

    4. Department of Pharmacy, Guangdong Food and Drug Vocational College, Guangzhou, 510520, China

      Ying Cui

    Author notes

    1. Jincan Chen and Yao Zhang contribute equally to this work.

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      Chen, J., Zhang, Y., Li, B. et al. A comparative study on in vitro cytotoxicity, cellular uptake, localization and apoptosis-inducing mechanism of two ruthenium(II) complexes. Transit Met Chem 43, 149–159 (2018). https://doi.org/10.1007/s11243-018-0203-y

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