bicyclol and Cell-Transformation--Neoplastic

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