PUBLICATION
Cyclometalated Ru(II) β-carboline complexes induce cell cycle arrest and apoptosis in human HeLa cervical cancer cells via suppressing ERK and Akt signaling
- Authors
- Chen, J., Deng, Y., Wang, J., Chen, S., Peng, F., He, X., Liu, M., Luo, H., Zhang, J., Chen, L.
- ID
- ZDB-PUB-210831-15
- Date
- 2021
- Source
- Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 26(7): 793-808 (Journal)
- Registered Authors
- Zhang, Jingjing
- Keywords
- Apoptosis, Cyclometalated Ru(II) complexes, ERK/Akt, ROS, β-Carboline alkaloids
- MeSH Terms
-
- Animals
- Antineoplastic Agents*/pharmacology
- Apoptosis
- Carbolines/pharmacology
- Cell Cycle Checkpoints
- Cell Line, Tumor
- Female
- HeLa Cells
- Humans
- Proto-Oncogene Proteins c-akt
- Reactive Oxygen Species
- Ruthenium*/pharmacology
- Signal Transduction
- Uterine Cervical Neoplasms*/drug therapy
- Zebrafish
- PubMed
- 34459988 Full text @ J. Biol. Inorg. Chem.
Citation
Chen, J., Deng, Y., Wang, J., Chen, S., Peng, F., He, X., Liu, M., Luo, H., Zhang, J., 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. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry. 26(7):793-808.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping