bicyclol and Liver-Neoplasms

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

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

The preventive effect of bicyclol, a novel anti-hepatitis drug, on hepatocarcinogenesis and its mechanism of action was studied in vitro. The results clearly indicated that bicyclol at non-toxic doses prevented the malignant transformation of WB-F344 cells (WB cells) induced by 3-methylcholanthrene (3MC) and 12-O-tetradecanoyl phorbol 13-acetate (TPA). Furthermore, bicyclol inhibited proliferation of quiescent WB cells stimulated by TPA and blocked TPA-induced down-regulation of the gap junctional intercellular communication (GJIC). Immunoblot analysis demonstrated that bicyclol exhibited a remarkable reversing effect on TPA-induced cPKC-alpha and phosphor-ERK1/2 expressions. In addition, bicyclol attenuated TPA-induced IkappaB-alpha degradation. In conclusion, our results support that bicyclol has chemopreventive action against hepatocarcinogenesis through inhibition of related signal transduction.

Topics: Animals; Antineoplastic Agents; Benz(a)Anthracenes; Biphenyl Compounds; Cell Communication; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; Colony-Forming Units Assay; Enzyme Induction; Epithelial Cells; I-kappa B Proteins; Liver Neoplasms; Male; Methylcholanthrene; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-KappaB Inhibitor alpha; Protein Kinase C-alpha; Rats; Rats, Inbred F344; Signal Transduction; Tetradecanoylphorbol Acetate

Oral administration of 100 and 200 mg/kg body weight/day of 4,4-dimethoxy-5,6,5', 6'-dimethylene-dioxy-2-hydroxymethyl-2'-carbonyl biphenyl, Bicyclol, inhibited rat hepatic preneoplastic lesions induced by diethylnitrosamine (DEN). Bicyclol reduced densities of number and area of gamma-glutamyltransferase positive foci, indexes for neoplastic hyperplasia; and also suppressed protein expressions for glutathione S transferase P isoform (GST-P) and alpha-fetal protein and mRNA for N-ras, c-myc and PKCalpha genes. With increases of total microsomal P450 and specific CYP2B1 activities in normal rat liver, Bicyclol enhanced particularly the denitrosation of DEN, a low toxic pathway of metabolism. There is a minor effect of Bicyclol on the deethylation of DEN to produce highly mutagenic metabolites. These results suggest that Bicyclol exists the ability of protecting hepatocytes from the mutagenicity of DEN. Such hypothesis was validated by the observation that Bicyclol inhibited DEN-induced unscheduled DNA synthesis, a DNA damage index, in primary cultured rat hepatocytes. More, in virto Bicyclol inhibited two-stages transformation of mice fibroblastic Balb/c 3T3 cells induced by 3-methylcholanthrene and tetradecanoyl-phorbol 13-acetate (TPA), and blocked the anchorage-independent growth of transformed cells in soft agar. Bicyclol also suppressed TPA-stimulated Balb/c 3T3 cell proliferation in both cell number and 3H-thymidine incorporation. Dot blot indicated that Bicyclol inhibited mRNA expressions of H-ras, c-myc and PKCalpha genes by TPA-stimulation. These data demonstrate that Bicyclol prevents carcinogens-induced animal neoplasm and cell malignant transformation via mechanisms at stages of initiation and promotion. It substantiates those evidences that Bicyclol would be used as potential a chemopreventive agent for hepatocarcinogenesis along with its major therapy against chronic anti-hepatitis.

Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Cell Transformation, Neoplastic; Chemoprevention; Diethylnitrosamine; Disease Models, Animal; Gene Expression Regulation; Genes, myc; Genes, ras; Liver Neoplasms; Male; Precancerous Conditions; Rats; Rats, Wistar; RNA, Messenger

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