Tanshinone Ⅱ_A exerts anti-hepatocellular carcinoma effects.
[TanshinoneⅡ_A exerts anti-hepatocellular carcinoma effects by inhibiting oxidative stress via PI3K/Akt and Nrf2/HO-1 signaling pathway].
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Abstract
This study aims to investigate the mechanism of tanshinoneⅡ_A(TanⅡ_A) in protecting mice from diethylinitrosamine(DEN)/carbon tetrachloride(CCl_4)/ethanol(C_2H_5OH)-induced hepatocellular carcinoma(HCC) and HepG2 cells from hydrogen peroxide(H_2O_2)-induced oxidative damage via the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt) and nuclear factor E2-related factor 2(Nrf2)/heme oxygenase 1(HO-1) signaling pathways. Sixty male C57BL/6J mice were grouped as follows: control, model, low, medium, and high-dose(10, 20, 40 mg·kg~(-1), respectively) TanⅡ_A, and colchicine(0.2 mg·kg~(-1)), with 10 mice in each group. The HCC model was established with DEN/CCl_4/C_2H_5OH for 20 weeks, and the mice were then euthanized for collection of blood and liver specimens. A protein-protein interaction(PPI) network of the targets of TanⅡ_A in the prevention of HCC was constructed. HepG2 cells were treated with 150μmol·L~(-1) H_2O_2 for the modeling of oxidative stress. The cell counting kit-8(CCK-8) was used to assess the effects of different concentrations(1, 2, 4μmol·L~(-1)) of TanⅡ_A on the relative viability of cells. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the liver tissue, and an automatic biochemical analyzer was used to measure the levels of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) in the mice serum. Relevant assay kits were used to measure the levels of reactive oxygen species(ROS), malondialdehyde(MDA), superoxide dismutase(SOD), glutathione(GSH), and glutathione peroxidase(GSH-Px) in the liver and cells. Immunohistochemistry, immunofluorescence assay, and Western blot were employed to determine the expression of phosphorylated PI3K(p-PI3K), PI3K, phosphorylated Akt(p-Akt), Akt, Nrf2, and HO-1. Compared with the control group, the model group exhibited typical pathological manifestations of liver cancer in the liver tissue, with elevated levels of ALT and AST in the serum, risen levels of ROS and MDA in the liver, and lowered levels of SOD and GSH in the liver. Compared with the control group, the HepG2 cells treated with H_2O_2 showed significantly decreased activities of SOD and GSH-Px and increased ROS and MDA levels. In the liver tissue and HepG2 cells, the modeling up-regulated the expression of p-PI3K and p-Akt while down-regulating the expression of Nrf2 and HO-1. Compared with the model group, different doses of TanⅡ_A reduced the levels of ALT and AST in the serum, elevated the levels of SOD, GSH, and GSH-Px in the liver tissue and cells, and lowered the ROS and MDA levels, which indicated significant alleviation of oxidative stress. The PPI network showed that Akt was a core target of the PI3K/Akt and Nrf2/HO-1 signaling pathways. Western blot, immunohistochemistry, and immunofluorescence assay results indicated that TanⅡ_A promoted the expression of Nrf2 and HO-1 while inhibiting the phosphorylation of PI3K and Akt. In conclusion, TanⅡ_A may delay the progression of HCC by inhibiting oxidative stress via the PI3K/Akt and Nrf2/HO-1 signaling pathways.
Affiliation
Meng Fang
External References
- PubMed ID:
- 39805761
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