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, NAD(P)H: 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.

Ruthenium (II) complex cis-[RuII(ŋ2-O2CC7H7O2)(dppm)2]PF6-hmxbato induces ROS-mediated apoptosis in lung tumor cells producing selective cytotoxicity

“…In this sense, the knowledge of molecular and biochemical mechanisms is of great relevance 3 . The probable mechanisms of action of many recently described ruthenium complexes involve apoptosis 27,32,[36][37][38] .…”

“…Other studies using ruthenium complexes have demonstrated its cytotoxic potential against different types of tumors 17,[61][62][63] and the DNA has been the target of these different complexes, which may culminate in cell death by apoptosis 37,43,50,64 . In this sense, it is worth mentioning that in addition to promoting apoptosis, hmxbato presented selective cytotoxicity for tumor cells, thus ensuring the survival of normal lung cells at the concentration of 3.8 µM.…”

Flexible ligated ruthenium(II) self-assemblies sensitizes glioma tumor initiating cells in vitro

“…Recent study also shows ruthenium complexes can block cell cycle progression and induces reactive oxygen species-reliant and mitochondria-based apoptosis [ 48 ]. It can also activate Nrf2 pathway for apoptosis primarily through the activation of caspase [ 49 ]. Another important report suggest that Ru-arene complexes are promising anti-cancer drugs that inhibit progression and metastasis by blocking multiple processes of cancers [ 50 ].…”

Dexmedetomidine impairs P‑glycoprotein‑mediated efflux function in L02 cells via the adenosine 5'‑monophosphate‑activated protein kinase/nuclear factor‑κB pathway

“…However, one aspect requires comment here. In this study, L02 cells instead of HepG2 cells were used as a model in vitro , as L02 is a normal human liver cell line that has been approved as suitable for studying liver function and various non-cancerous liver diseases in vitro ( 26 – 29 ). For example, Liu et al examined the effect of synthetic muscone on the expression of the CYP1A2 and CYP3A4 enzymes in L02 cells, as well as in the liver tissue of Kunming mice, and demonstrated that muscone can induce the hepatic expression of CYP1A2 and CYP3A4 both in vitro and in vivo ( 29 ).…”