bicyclol and Carcinoma--Hepatocellular

Bicyclol, a synthetic hepatoprotective and anti-inflammatory agent approved in China, was widely used to treat various hepatitis accompanied by elevated serum aminotransferases. However, the pharmacological effects and mechanisms of bicyclol on advanced liver diseases, such as fibrosis/cirrhosis and hepatocellular carcinoma (HCC), remain to be explored. Here, we revealed that bicyclol prevents from formatting severe fibrosis, slows the progression of moderate liver fibrosis, accelerates the regression of moderate liver fibrosis, decreases the malignancy of HCC in rat models induced by diethylnitrosamine (DEN), and also blocks steatohepatitis to HCC in mice induced by western diet plus carbon tetrachloride and DEN. The detailed pharmacological mechanism showed that bicyclol alleviates chronic progressive liver diseases by inhibiting the levels of IL-6 and subsequent phosphorylated STAT3. Conclusion: Bicyclol plays significant protective roles in multiply stages of fibrosis/cirrhosis-HCC and nonalcoholic fatty liver disease-related HCC via inhibiting IL-6/STAT3 signaling pathway. Therefore, bicyclol might be a promising therapeutic strategy for treating advanced liver diseases.

Topics: Animals; Biphenyl Compounds; Carcinoma, Hepatocellular; Disease Models, Animal; Interleukin-6; Liver; Liver Cirrhosis; Liver Neoplasms; Mice; Rats; Signal Transduction

The aim of this study was to determine the effect of bicyclol against cisplatin-induced hepatotoxicity and the influence on the antitumour capacity of cisplatin in hepatocarcinoma 22 (H22) tumour-bearing mice. ICR mice were treated with bicyclol (250 mg/kg, orally) 2 hr before the injection of cisplatin (5 mg/kg, intraperitoneally) for 5 days (once daily) after H22 tumour cells were implanted. All animals were killed on the fifth day after cisplatin treatment and tumour weight of each animal was measured. Liver pathological changes were examined by light microscopy and biochemical assay. The expressions of liver inducible nitric oxide synthase (iNOS and nitric oxide synthase 2) and 3-nitrotyrosine were assessed by Western blotting. Bicyclol showed a significant protection as evidenced by the decrease of elevated serum aminotransferases and lactate dehydrogenase, and improvement of histopathological injury induced by cisplatin. The formation of liver malondialdehyde with a concomitant reduction of reduced glutathione was also inhibited by bicyclol, while the activities of liver superoxide dismutase, catalase and glutathione peroxidase were all increased, respectively. In addition, the over expressions of liver iNOS and 3-nitrotyrosine were suppressed by bicyclol. The administration of bicyclol had no affect on the anti-tumour capacity of cisplatin in mice bearing H22 tumour. The hepatoprotective action of bicyclol provides a new approach for preventing the hepatotoxicity induced by cisplatin in the clinic.

Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Cisplatin; Drug Interactions; Gene Expression Regulation; L-Lactate Dehydrogenase; Liver; Liver Diseases; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred ICR; Nitric Oxide Synthase Type II; Transaminases; Tyrosine

To assess the anti-invasion effect of bicyclol (1) and its mechanism in human hepatocellular carcinoma (HCC) MHCC97-H cells with high metastatic potential. MTT assay was performed to evaluate the cytotoxicity of 1 to MHCC97-H cells and its inhibitory effect on the adhesion of these cells to laminin (LN) and fibronectin (FN). The anti-invasion effect of 1 was detected in an experiment using a transwell chamber. Transcription of vascular endothelial growth factor (VEGF), nm23-H1, and urokinase-type plasminogen activator receptor (uPAR) mRNAs was determined by an RT-PCR assay. The secretion and expression of alpha-fetoprotein (AFP) were analyzed by ELISA and flow cytometry, respectively. At concentrations of 10, 50, and 100 mumol/l, 1 obviously inhibited the adhesion of the MHCC97-H cells to LN and FN. The rates of inhibition of MHCC97-H cell invasion by 50 and 100 mumol/l for 1 were 37.3 and 50.2%, respectively. Drug 1 also decreased the expressions of VEGF, nm23-H1, and uPAR mRNA and the secretion of AFP in MHCC97-H cells. At low cytotoxic concentrations, the anti-hepatitis drug 1 demonstrated a significant anti-invasive effect in human HCC MHCC97-H cells with high metastatic potential. The inhibition of the expressions of VEGF, nm23-H1, and uPAR should contribute, at least in part, to the anti-invasion property of 1.

Topics: alpha-Fetoproteins; Biphenyl Compounds; Carcinoma, Hepatocellular; Cell Adhesion; Hepatitis; Humans; Liver Neoplasms; Molecular Structure; Neoplasm Invasiveness; Neoplasm Metastasis; Sequence Homology, Nucleic Acid; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator; Vascular Endothelial Growth Factor A

Hepatocellular carcinoma (HCC) is a major health problem worldwide, involving more than 620,000 new cases yearly, with chronic HBV and HCV infection being the most common causes. Because most patients are diagnosed in an advanced state which is usually not amenable to curative therapy, prevention should be the main focus for reducing the HCC incidence and its related morbidity and mortality. Strategies of HCC prevention can focus on each single risk factor, with antiviral therapy against chronic hepatitis B and hepatitis C as well as suppression of the progression of common liver diseases being the most important and effective measures. Bicyclol, a drug that can improve liver function and inhibit HBV replication, may be a useful agent for the chemopreventive of HCC, as indicated by a recent study by Zhu et al. Bicyclol can act on the initiation and promotion stages of hepatocarcinogenesis by preventing malignant transformation of hepatic cells. It may also enhance the liver's capacity of detoxification and inhibit DNA mutations. More clinical studies are needed to further demonstrate the efficacy and molecular mechanisms of this agent on HCC chemoprevention.

Topics: Biphenyl Compounds; Carcinoma, Hepatocellular; Chemoprevention; Humans; Liver Neoplasms