isofraxidin and Liver-Neoplasms

Aidi injection (ADI) is a popular anti-tumor Chinese patent medicine, widely used in clinics for the treatment of hepatocellular carcinoma (HCC) with remarkable therapeutic effects through multiple targets and pathways. However, the scientific evidence of the synergistic role of the complex chemical component system and the potential mechanism for treating diseases are ignored and remain to be elucidated.. This study aimed to elucidate and verify the cooperative association between the potential active ingredient of ADI, which is of significance to enlarge our understanding of its anti-HCC molecular mechanisms.. Firstly, the anti-HCC effect of ADI was evaluated in various HCC cells and the zebrafish xenograft model. Subsequently, a variety of bioinformatic technologies, including network pharmacology, weighted gene co-expression network analysis (WGCNA), meta-analysis of gene expression profiles, and pathway enrichment analysis were performed to construct the competitive endogenous RNA (ceRNA) network of ADI intervention in HCC and to establish the relationship between the critical targets/pathways and the key corresponding components, which were involved in ADI against HCC in a synergistic way and were validated by molecular biology experiments.. ADI exerted remarkable anti-HCC in vitro cells and in vivo zebrafish model, especially that the Hep 3B2.1-7 cell showed substantial sensibility to ADI. The ceRNA network revealed that the EGFR/PI3K/AKT signaling pathway was identified as the promising pathway. Furthermore, the meta-analysis also demonstrated the critical role of BIRC5 and FEN1 as key targets. Finally, the synergistic effect of ADI was revealed by discovering the inhibitory effect of cantharidin on BIRC5, formononetin on FEN1 and EGFR, as well as isofraxidin on EGFR.. Our study unveiled that the incredible protective effect of ADI on HCC resulted from the synergistic inhibition effect of cantharidin, formononetin, and isofraxidin on multiple targets/pathways, including BIRC5, FEN1, and EGFR/PI3K/AKT, respectively, providing a scientific interpretation of ADI against HCC and a typical example of pharmacodynamic evaluation of other proprietary Chinese patent medicine.

Topics: Animals; Cantharidin; Carcinoma, Hepatocellular; ErbB Receptors; Flap Endonucleases; Humans; Liver Neoplasms; Nonprescription Drugs; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Survivin; Zebrafish

7-Hydroxy-6,8-dimethoxy-2H-1-benzopyran-2-one (isofraxidin) is a major coumarin component isolated from the stem bark of Acanthopanax senticosus, a widely used Chinese medicinal herb. We investigated isofraxidin in its anti-tumor effects on human hepatoma cell lines HuH-7 and HepG2. Isofraxidin significantly inhibited hepatoma cell invasion, without affecting cell attachment or growth. Expression of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-7 (MMP-7) in hepatoma cells was inhibited by isofraxidin at the both mRNA and protein levels. This inhibition tended to be greater in cells inoculated at low density than in those at high density. Isofraxidin showed an inhibitory effect on the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in hepatoma cells, whereas activator protein-1 (AP-1) DNA binding activity, nuclear factor-kappa B (NF-κB) nuclear translocation, and inhibitory kappa B (IκB) degradation were affected very little. These results indicate that isofraxidin inhibits expression of MMP-7 and in vitro cell invasion at a non-toxic level through inhibiting ERK1/2 phosphorylation in hepatoma cell lines, which suggest isofraxidin might become an effective agent for suppressing hepatoma cell invasion.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Line, Tumor; Coumarins; Eleutherococcus; Hep G2 Cells; Humans; Liver Neoplasms; Matrix Metalloproteinase Inhibitors; Mitogen-Activated Protein Kinase 3; Neoplasm Invasiveness; Phosphorylation; Phytotherapy; Plant Bark; Plant Extracts; Plant Stems; Tetradecanoylphorbol Acetate