Activation of reactive oxygen species-mediated mitogen-activated protein kinases pathway regulates both extrinsic and intrinsic apoptosis induced by arctigenin in Hep G2

Abstract

Objectives Arctigenin (ARG) has been proved to inhibit the viability of hepatocellular carcinoma (HCC) via inducing apoptosis. However, the precise mechanism remains unknown. The present study was aimed to further investigate the mechanism of ARG against HCC in vitro and in vivo. Methods Arctigenin was applied in vitro and in vivo. Western blotting, immunohistochemistry, etc., were used to investigate the mechanisms. Key findings The time‐dependent enhancement of Bax/Bcl‐2 ratio, cytochrome c release, Fas and FasL levels, caspase cascade activation and the loss in the mitochondrial out membrane potential indicated that both intrinsic and extrinsic apoptotic pathways were triggered by ARG. Moreover, Jun NH2‐terminal kinase (JNK) and p38 phosphorylated time‐dependently. And inhibition of the phosphorylation of either p38 or JNK led to a significant reduction in HepG2 apoptosis, owing to the crucial roles of p38 and JNK played in regulating the apoptosis pathways. In addition, ARG increased the generation of reactive oxygen species (ROS) in HepG2 cells, while the antioxidant N‐acetyl cysteine almost reversed ARG‐induced JNK and p38 activation, and dramatically decreased cell apoptosis. In vivo, ARG increased the cell apoptosis in tumour tissues, and p‐p38, p‐JNK and Bax were significantly upregulated. Conclusions Our findings demonstrated that ARG induced apoptosis in HCC via ROS‐mediated mitogen‐activated protein kinases apoptosis pathway.

Lignans as Pharmacological Agents in Disorders Related to Oxidative Stress and Inflammation: Chemical Synthesis Approaches and Biological Activities

“…Arctigenin also induced apoptosis of human breast cancer MDA-MB-231 cells via the triggering of the mitochondrial caspase-independent ROS/p38 MAPK pathway and epigenetic Bcl-2 downregulation [ 81 ]. In another study, arctigenin promoted apoptosis in human hepatocellular carcinoma-related Hep G2 cells via the enhancement of theROS-mediated mitochondrial dysfunction, p38 and JNK and MAPK pathways activation as well as CYP450 and Bax upregulation [ 86 ].…”

Changes in Oxidative Phosphorylation Activity in Fibroblasts at p38 MAPK Pathway Inhibition

“…(28) In addition, the study conducted on hepatocarcinoma cells demonstrated a positive dependence of CcO subunit IV expression from p38 MAPK activity. (29) Our results demonstrate an increase in CcO levels during p38 MAPK inhibition, which may indicate that p38 MAPK negatively regulates the CcO expression in peritoneal fibroblasts of adult animals ( Figure 2C).…”

Simultaneous Treatment with P53 Overexpression and Interferon γ Exerts a Dramatic Increase in Apoptosis Induction of U87 Cells

“…When stimulated, they cause conversion of inactive pro-caspases-8 and -10 into active initiator, which can envisage activation of Bid (a pro-apoptotic Bcl2 family protein) and release of cytochrome C from mitochondria into the cytoplasm [17]. In the intrinsic pathway, mitochondria play a crucial role; and after stimulation, cytochrome C, Apaf-1, and caspase-9 are released to the cytoplasm, where the association of calcium ions forms apoptosome and in turn results in active caspase-3 [16][17][18][19][20][21]. Similarly, our western blot results revealed that after GMJ.2021;10:e2270 www.gmj.ir treatment of U87 cells with IFNγ and/or P53 overexpression, the expression level of cleaved caspase-3 increased (this may be a reliable joint venture between these two treatments).…”