fumonisin-b1 and Cell-Transformation--Neoplastic

Some venom components are known to present potential biological activities that are useful as tools in therapeutics. In this study anti-tumoral activity of Androctonus australis hector (Aah) venom and its purified fraction on early step of hepato-carcinogenesis initiated by Fumonisin (FB1), was tested. Initiated hepatic tumor was assessed in mice by decreased doses of Fumonisin B1 associated to phenobarbital. Scorpion venom was used to investigate its activity on initiated tumor by FB1. Evaluation of oxidative unbalance, enzymatic activities and DNA quantification in the liver were correlated with tissue analysis. Obtained results showed that the initiated pathogenesis by FB1 at seven months was characterized by tissue alterations and biomarker variations. These alterations were characterized by atypical lesions such as muffled nucleus, karyo- and cyto-megaly; up normal and large number of nuclei into hepatocytes. These alterations were confirmed by DNA alteration. An unbalance of oxidative status was also observed, characterized by an increased levels of respectively oxidant (NO and MDA) and antioxidant (GSH and catalase activity) mediators. Aah venom and its non-toxic fraction used at low doses seemed to be able to restore partially the hepatic altered tissue induced by FB1. Decreased levels of oxidative and anti-oxidative mediators were also observed. DNA in hepatocytes returned also to the physiological values. Structure of hepatic tissue showed restoration of some alterations such as karyo- and cyto-megaly; decrease of polyploidy hepatocytes induced by FB1. Aah venom and its non-toxic fraction seem to contain some bioactive components with anti-tumoral activity. Purification of this activity from non-toxic fraction F1 could be of interest to identify the components with anti-tumoral activities.

Topics: Animals; Carcinogens, Environmental; Cell Transformation, Neoplastic; Female; Fumonisins; Hepatocytes; Liver Neoplasms, Experimental; Malondialdehyde; Mice; Nitric Oxide; Scorpion Venoms; Scorpions

Fumonisin B₁ (FB₁), a common mycotoxin contaminant of maize, is known to inhibit sphingolipid biosynthesis and has been implicated in hepatocellular carcinoma promoting activity in humans and animals. MicroRNAs (miRNA) are small noncoding RNAs that regulate gene expression via translational repression. Human cytochrome P450 (CYP1B1) is highly expressed in oestrogen target tissues and catalyzes the metabolic activation of many procarcinogens. The aim of our study was to investigate the effect of FB₁ on miR-27b suppression and its effect on CYP1B1 modulation in a human hepatoma cell line (HepG2). MiR27b and CYP1B1 expressions were evaluated in HepG2 cells by quantitative PCR. In order to directly assess the effect of miR-27b on CYP1B1 mRNA levels, cells were transfected with the mimic to miR-27b. CYP1B1 protein expression was measured using Western blot. FB₁ significantly down-regulated (11-fold) expression of miR-27b in HepG2 cells; whilst CYP1B1 mRNA and protein expression was significantly upregulated by 1.8-fold and 2.6-fold, respectively. CYP1B1 is post-transcriptionally regulated by miR-27b after HepG2 exposure to FB₁. FB₁-induced modulation of miR-27b in hepatic cells may be an additional mode of hepatic neoplastic transformation.

Topics: Aryl Hydrocarbon Hydroxylases; Carcinogens, Environmental; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cluster Analysis; Cytochrome P-450 CYP1B1; Down-Regulation; Enzyme Induction; Fumonisins; Hep G2 Cells; Hepatocytes; Humans; Liver Neoplasms; MicroRNAs; Molecular Mimicry; Neoplasm Proteins; RNA, Messenger; Transfection

Mycotoxins that commonly contaminate staple food grains pose a health hazard to animals and humans. Fumonisin B1 (FB1), a mycotoxin produced by Fusarium verticillioides, causes equine leukoencephalomalacia and porcine pulmonary edema and has been implicated in the etiology of esophageal cancer (EC) in the Transkei, South Africa. Various studies have indicated that nitrosamines induce EC, and F. verticillioides enhancement of nitrosamine-induced EC in rats has been reported. Dietary catechol (CAT), a constituent of cigarette smoke, was previously found to be a cocarcinogen with methyl-N-nitrosamine for inducing esophageal tumors in rats. In the present study we therefore investigated the cytotoxic effects of FB1, diethylnitrosamine (DEN), and CAT on a human esophageal epithelial cell line (SNO) using the methylthiazol tetrazolium assay. For each treatment, toxin concentrations ranged from 2.165 to 34.64 micro M. The results showed that the cytotoxic response of SNO cells was highest in cells treated with 34.64 micro M FB1. SNO cells treated with DEN + FB1 showed greater cytotoxicity than did cells treated with FB1 alone, whereas FB1 appeared to inhibit the cytotoxic effect exerted by CAT alone. The results of this study provide further evidence for the involvement of FB1 in the etiology of esophageal carcinoma.

Topics: Alkylating Agents; Carboxylic Acids; Carcinogens, Environmental; Catechols; Cell Transformation, Neoplastic; Diethylnitrosamine; Dose-Response Relationship, Drug; Epithelial Cells; Esophageal Neoplasms; Esophagus; Fumonisins; Humans; Tumor Cells, Cultured

Data from the National Toxicology Program's carcinogenesis study of fumonisin B1 in B6C3F1 mice, conducted at the National Center for Toxicological Research, were used to fit the Moolgavkar-Venzon-Knudson (MVK) two-stage, clonal-expansion model of carcinogenesis. In addition to tumour data from the conventional 2-year bioassay, the study included data on tissue weights, cell proliferation, cell death, and sphingolipid metabolism in primary target organs. The model was used to predict 2-year liver tumour rates in female and male mice based on differences among dose groups in the effect of fumonisin B1 on the growth of normal tissue and on the proliferation of preneoplastic cells as a compensatory response to sphinganine-induced cell death. Fumonisin B1 was assumed to be non-genotoxic, i.e. the model did not include any effect of fumonisin B1 on either of the two mutation rates of the MVK model. The model was able to reproduce reasonably well the observed tumour rates in both female and male mice, predicting substantially increased rates above background only at the highest doses of fumonisin B1 in females.

Topics: Animals; Body Weight; Carboxylic Acids; Carcinogens, Environmental; Cell Death; Cell Division; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Female; Food Contamination; Fumonisins; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred Strains; Models, Biological; Mycotoxins; Organ Size; Risk Assessment; Sex Factors; Sphingosine

The chemotherapeutic agent CPT-11 induces apoptotic cell death in various cells. In the present study we examined the effect of CPT-11 in rat pheochromocytoma PC12 cells. When PC12 cells were treated with CPT-11, two distinct reactions were encountered. A high dose of CPT-11 induced apoptotic cell death mediated by caspase cascade, whereas a low dose of CPT-11 induced irreversible cell morphological changes. The cell shape of the transformed PC12 cells was similar to fibroblasts, and these were termed FLTP12 (fibroblast-like transformed PC12). FLTP12 cells showed some differences from the original PC12 cells. In addition, cultured media of passed FLTP12 cells induced same cell transformation in PC12 cells. To examine how this transformation may be triggered, the possible involvement of a growth factor(s) was investigated. Among those tested, the possible involvement of basic fibroblast growth factor (basic-FGF) was observed, whereas basic FGF antibody did not affect the induction of cell transformation. Molecular sieve analysis revealed that transformation-inducing factor is large molecule protein like cell attachment factors (>100K), and we demonstrated the direct involvement of tenascin in the transformation of PC12 cell.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Camptothecin; Carboxylic Acids; Caspase Inhibitors; Caspases; Cell Division; Cell Nucleus; Cell Survival; Cell Transformation, Neoplastic; Culture Media, Conditioned; Dactinomycin; DNA Fragmentation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fibroblasts; Fumonisins; Irinotecan; Oligopeptides; PC12 Cells; Rats; Tenascin; Tumor Necrosis Factor-alpha

The capacity of fumonisin B1 (FB1) to induce morphological transformation of cultured mammalian cells was assessed using BALB/3T3 A31-1-1 mouse embryo cells. FB1 with 90% purity was prepared from Fusarium proliferatum grown on whole corn. Cell growth was not inhibited by 48 hr of exposure at concentrations up to 1000 micrograms/ml. Moderate inhibition was induced by 6 days of exposure. In transformation assays with a 48-hr exposure, increases in transformed foci were observed at some concentrations; however, the responses were not reproducible. Prolonged exposure for up to 4 wk at 10, 100 and 500 micrograms/ml failed to induce increases in transformed foci. Analysis of combined results showed that only the increase induced by a 48-hr exposure at 500 micrograms/ml was significant. A trend test indicated the lack of a dose response for concentrations of 10-1000 micrograms/ml. FB1 seems to lack in vitro transforming activity.

Topics: Animals; Carcinogens, Environmental; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Dose-Response Relationship, Drug; Fumonisins; Fusarium; Mice; Mice, Inbred BALB C; Mycotoxins; Teratogens; Zea mays