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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

Chen, J., Deng, Y., Wang, J., Chen, S., Peng, F., He, X., Liu, M., Luo, H., Zhang, J. and Chen, L. (2021) Cyclometalated Ru(II) β-carboline complexes induce cell cycle arrest and apoptosis in human HeLa cervical cancer cells via suppressing ERK and Akt signaling. JBIC Journal of Biological Inorganic Chemistry .

Link to Published Version: https://doi.org/10.1007/s00775-021-01894-4
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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.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Molecular Medicine and Innovative Therapeutics (CMMIT)
Publisher: Springer Nature
Copyright: © 2021 Springer Nature Switzerland AG.
URI: http://researchrepository.murdoch.edu.au/id/eprint/62110
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