Baishouwu Extract Suppresses the Development of Hepatocellular Carcinoma via TLR4/MyD88/NF-κB Pathway

Abstract

Purpose: The root of Cynanchum auriculatum Royle ex Wight, known as Baishouwu, has been widely used for a tonic supplement since ancient times. The current study was performed to explore the effect of Baishouwu extract on the development of experimental hepatocellular carcinoma (HCC) and the potential mechanism involved. Methods: Rats were injected diethylnitrosamine (DEN) to initiate the multistep hepatocarcinogenesis. Animals were treated concurrently with Baishouwu extract given daily by oral gavage for 20 weeks to evaluate its protective effects. Time series sera and organ samples from each group were collected to evaluate the effect of Baishouwu extract on hepatic carcinogenesis. Results: It was found that Baishouwu extract pretreatment successfully attenuated liver injury induced by DEN, as shown by decreased levels of serum biochemical indicators (AST, ALT, ALP, TP, and T-BIL). Administration of Baishouwu extract inhibited the fibrosis-related index in serum and live tissue, respectively from inflammation stage to HCC stage after DEN treatment. It significantly reduced the incidence and multiplicity of DEN-induced HCC development in a dose-dependent manner. Macroscopic and microscopic features suggested that pretreatment with Baishouwu extract for 20 weeks was effective in inhibiting DEN-induced inflammation, liver fibrosis, and HCC. Furthermore, TLR4 overexpression induced by DEN was decreased by Baishouwu extract, leading to the markedly down-regulated levels of MyD88, TRAF6, NF-κB p65, TGF-β1 and α-SMA in hepatitis, cirrhosis, and hepatocarcinoma. Conclusion: In conclusion, Baishouwu extract exhibited potent effect on the development of HCC by altering TLR4/MyD88/ NF-κB signaling pathway in the sequence of hepatic inflammation-fibrosis-cancer, which provided novel insights into the mechanism of Baishouwu extract as a candidate for the pretreatment of HCC in the future.

Hypoxia-Inducible Ubiquitin Specific Peptidase 13 Contributes to Tumor Growth and Metastasis via Enhancing the Toll-Like Receptor 4/Myeloid Differentiation Primary Response Gene 88/Nuclear Factor-κB Pathway in Hepatocellular Carcinoma

“…HCC (Kang et al, 2018;Ding et al, 2019;Zhang et al, 2020). The inhibition of the TLR4/MyD88 pathway represses the occurrence and progression of HCC (Ding et al, 2019;Zhang et al, 2020).…”

“…HCC (Kang et al, 2018;Ding et al, 2019;Zhang et al, 2020). The inhibition of the TLR4/MyD88 pathway represses the occurrence and progression of HCC (Ding et al, 2019;Zhang et al, 2020). NF-κB-mediated EMT process contributes to HCC progression, and the suppression of the NF-κB pathway represses EMT and invasion of tumor cells (Song et al, 2014;Zhu et al, 2016).…”

“…The inactivation of the TLR4/MyD88 pathway by geniposide reduced signal transducer and activator of transcription 3 (STAT3)/Sp1-dependent vascular endothelial growth factor (VEGF) production in HCC cells (Zhang et al, 2020). A previous study has demonstrated that Baishouwu extract suppresses the initiation and progression of HCC via inhibiting the TLR4/MyD88/NF-κB pathway (Ding et al, 2019). Moreover, hypoxia-inducible factor-1α (HIF-1α)mediated TLR4/MyD88 pathway participates in hypoxia-induced HCC cell proliferation, migration, and invasion (Zhang et al, 2016).…”

Versatile role of curcumin and its derivatives in lung cancer therapy

“…Song, Liu, & Yu, 2020). On the contrary, Toll‐like receptor 4 (TLR4)/MyD88 plays a significant role in inflammation and enhances the malignancy and proliferation of different cancers (Ding, Peng, Ding, & Peng, 2019; Koliaraki et al, 2019). Both EGFR and TLR4 can act as upstream mediators to stimulate epithelial‐to‐mesenchymal transition (EMT) in cancer cells, leading to their malignant behavior (Y. Cao, Shen, Zhang, Zhang, & Zhang, 2019; Shao et al, 2019).…”

Caudatin Isolated from Cynanchum auriculatum Inhibits Breast Cancer Stem Cell Formation via a GR/YAP Signaling

“…In the Chinese and Korean pharmacopeia, the tuberous root of C. auriculatum named "Baishouwu" or "Baekshuoh" has been used as a traditional herbal medicine to treat gastric ulcers, neurasthenia, edema and nephritis [2,3]. Pharmacological and phytochemical studies have reported that C. auriculatum has high application and economic value and displays beneficial antiviral [4], gastroprotective [5], antioxidant [6], antidepressant [7] and antitumor activities [8]. Caudatin is a type of C-21 steroid mainly isolated from C. auriculatum, which has been shown to have effective activity against cancers of different origins [9,10].…”