title: Ruthenium Complexes Induce HepG2 Human Hepatocellular Carcinoma Cell Apoptosis and Inhibit Cell Migration and Invasion through Regulation of the Nrf2 Pathway.
abstract: Ruthenium (Ru) complexes are currently the focus of substantial interest because of their potential application as chemotherapeutic agents with broad anticancer activities. This study investigated the in vitro and in vivo anticancer activities and mechanisms of two Ru complexes-2,3,7,8,12,13,17,18-Octaethyl-21H,23H-porphine Ru(II) carbonyl (Ru1) and 5,10,15,20-Tetraphenyl-21H,23H-porphine Ru(II) carbonyl (Ru2)-against human hepatocellular carcinoma (HCC) cells. These Ru complexes effectively inhibited the cellular growth of three human hepatocellular carcinoma (HCC) cells, with IC50 values ranging from 2.7-7.3 μM. In contrast, the complexes exhibited lower toxicity towards L02 human liver normal cells with IC50 values of 20.4 and 24.8 μM, respectively. Moreover, Ru2 significantly inhibited HepG2 cell migration and invasion, and these effects were dose-dependent. The mechanistic studies demonstrated that Ru2 induced HCC cell apoptosis, as evidenced by DNA fragmentation and nuclear condensation, which was predominately triggered via caspase family member activation. Furthermore, HCC cell treatment significantly decreased the expression levels of Nrf2 and its downstream effectors,
  quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO1). Ru2 also exhibited potent in vivo anticancer efficacy in a tumor-bearing nude mouse model, as demonstrated by a time- and dose-dependent inhibition on tumor growth. The results demonstrate the therapeutic potential of Ru complexes against HCC via Nrf2 pathway regulation.
authors.affiliation: Department of Oncology, Nanhai Hospital of Southern Medical University, Foshan 528200, China. lu_yiyu@163.com.
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Oncology, Nanhai Hospital of Southern Medical University, Foshan 528200, China. shenting0479@163.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Shen
authors.affiliation: Department of Oncology, Nanhai Hospital of Southern Medical University, Foshan 528200, China. yanghua9206@163.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Oncology, Nanhai Hospital of Southern Medical University, Foshan 528200, China. guweiguang1969@163.com.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Gu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D012428:Ruthenium / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009363:Neoplasm Proteins; D009942:Organometallic Compounds; D012428:Ruthenium
keywords: Nrf2; Ru complex; apoptosis