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Cyclometalated Ru(II) β-carboline complexes induce cell cycle arrest and apoptosis in human HeLa cervical cancer cells via suppressing ERK and Akt signaling

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Abstract

Two new cyclometalated Ru(II)-β-carboline complexes, [Ru(dmb)2(Cl-Ph-βC)](PF6) (dmb = 4,4′-dimethyl-2,2′-bipyridine; Cl-Ph-βC = Cl-phenyl-9H-pyrido[3,4-b]indole; RuβC-3) and [Ru(bpy)2(Cl-Ph-βC)](PF6) (bpy = 2,2′-bipyridine; RuβC-4) were synthesized and characterized. The Ru(II) complexes display high cytotoxicity against HeLa cells, the stabilized human cervical cancer cell, with IC50 values of 3.2 ± 0.4 μM (RuβC-3) and 4.1 ± 0.6 μM (RuβC-4), which were considerably lower than that of non-cyclometalated Ru(II)-β-carboline complex [Ru(bpy)2(1-Py-βC)] (PF6)2 (61.2 ± 3.9 μM) by 19- and 15-folds, respectively. The mechanism studies indicated that both Ru(II) complexes could significantly inhibit HeLa cell migration and invasion, and effectively induce G0/G1 cell cycle arrest. The new Ru(II) complexes could also trigger apoptosis through activating caspase-3 and poly (ADP-ribose) polymerase (PARP), increasing the Bax/Bcl-2 ratio, enhancing reactive oxygen species (ROS) generation, decreasing mitochondrial membrane potential (MMP), and inducing cytochrome c release from mitochondria. Further research revealed that RuβC-3 could deactivate the ERK/Akt signaling pathway thus inhibiting HeLa cell invasion and migration, and inducing apoptosis. In addition, RuβC-3-induced apoptosis in HeLa cells was closely associated with the increase of intracellular ROS levels, which may act as upstream factors to regulate ERK and Akt pathways. More importantly, RuβC-3 exhibited low toxicity on both normal BEAS-2B cells in vitro and zebrafish embryos in vivo. Consequently, the developed Ru(II) complexes have great potential on developing novel low-toxic anticancer drugs.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (21701034), the Natural Science Foundation of Guangdong Province (2020A1515010444), the Science and technology program of Guangdong Province (2019B090905011), Discipline Construction Project of Guangdong Medical University (4SG21004G), the Fund of Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang) (ZJW-2019-007), Major Scientific Research Project in Guangdong Province (Special Innovative Project) (2018KQNCX100), the Medical Scientific Research Foundation of Guangdong Province of China (A2020414), and the University Student Innovation Experiment Program.

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Authors and Affiliations

  1. Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang, 524023, Guangdong, China

    Jincan Chen, Hui Luo & Lanmei Chen

  2. Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, China

    Jincan Chen, Yuanyuan Deng, Jie Wang, Fa Peng, Xuerong He, Meijun Liu, Hui Luo & Lanmei Chen

  3. The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, 524023, Guangdong, China

    Jincan Chen, Hui Luo & Jingjing Zhang

  4. Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, 6150, Australia

    Suxiang Chen

  5. Affiliated Hospital of Guangdong Medical University & Key Laboratory of Zebrafish Model for Development and Disease of Guangdong Medical University, Zhanjiang, 524001, China

    Jingjing Zhang

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  1. Jincan Chen
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Chen, J., Deng, Y., Wang, J. et al. Cyclometalated Ru(II) β-carboline complexes induce cell cycle arrest and apoptosis in human HeLa cervical cancer cells via suppressing ERK and Akt signaling. J Biol Inorg Chem 26, 793–808 (2021). https://doi.org/10.1007/s00775-021-01894-4

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