Flubendazole is a widely used anthelmintic drug belonging to benzimidazole group. The molecular mechanism of action of flubendazole is based on its specific binding to tubulin, which results in disruption of microtubule structure and function, and in the interference with the microtubule-mediated transport of secretory vesicles in absorptive tissues of helminths. The microtubule-disrupting properties of benzimidazole derivatives raised recently interest in these compounds as possible anti-cancer agents. In this minireview flubendazole effects towards selected human malignant cells including myeloma, leukemia, neuroblastoma, breast cancer, colorectal cancer and melanoma are discussed along with basic data on its pharmacokinetics, metabolism and toxicity.
- MeSH
- Leukemia drug therapy MeSH
- Humans MeSH
- Mebendazole analogs & derivatives therapeutic use MeSH
- Microtubules metabolism MeSH
- Multiple Myeloma drug therapy MeSH
- Cellular Senescence drug effects MeSH
- Tubulin metabolism MeSH
- Cell Survival MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The effect of flubendazole (FLU) therapy on in vitro FLU biotransformation and the activities of selected biotransformation enzymes were investigated in male and female lambs. Four experimental groups were used: control (untreated) ewes and rams and FLU-treated ewes and rams (orally, 15 mg/kg per day, for three consecutive days). Subcellular fractions were prepared from liver and intestinal mucosa 24 h after the final dosage was administered. Activities of cytochromes P450 (CYP), flavine monooxygenases (FMO), carbonyl reducing enzymes, UDP-glucuronosyl transferase (UGT) and glutathione S-transferase were tested. Significant gender differences were observed for FMO-mediated activity (2-fold higher in ram lambs) and UGT activity (up to 30% higher in ewe lambs), but no gender differences were observed in FLU metabolism. FLU-treatment of lambs moderately changed the activities of some CYPs, FMO, and UGT in liver microsomes. In vitro FLU reduction was not altered in the liver, but was slightly higher in the small intestine of FLU pre-treated lambs. This correlated with the higher carbonyl reductase activities measured in the gut mucosa of these animals.
- MeSH
- Antinematodal Agents metabolism MeSH
- Biotransformation MeSH
- Cytosol metabolism MeSH
- Liver metabolism MeSH
- Mebendazole analogs & derivatives metabolism pharmacology MeSH
- Sheep MeSH
- Sex Characteristics MeSH
- Intestine, Small metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Haemonchus contortus is one of the most pathogenic parasites of small ruminants (e.g., sheep and goat). The treatment of haemonchosis is complicated because of frequent resistance of H. contortus to common anthelmintics. The development of resistance can be facilitated by the action of drug metabolizing enzymes of parasites that can deactivate anthelmintics and thus protect parasites against the toxic effect of the drug. The aim of this project was to investigate the Phase I biotransformation of benzimidazole anthelmintic flubendazole in H. contortus and to determine the biotransformation of other model xenobiotics. For this purpose, in vitro (subcellular fractions of H. contortus homogenate) as well as ex vivo (live nematodes cultivated in flasks with medium) experiments were used. The results showed that cytosolic NADPH-dependent enzymes of H. contortus metabolize flubendazole via reduction of its carbonyl group. The apparent kinetic parameters of this reaction were determined (V'max=39.8+/-2.1 nM min(-1), K'm=1.5+/-0.3 microM). The reduction of flubendazole in H. contortus is stereospecific, the ratio of (-):(+) enantiomers of reduced flubendazole formed was 90:10. Reduced flubendazole was the only Phase I metabolite found. Effective reduction of other xenobiotics with carbonyl group (metyrapon, daunorubicin, and oracin) was also found. Significant activity of carbonyl-reducing enzymes may be important for H. contortus to survive the attacks of anthelmintics or other xenobiotics with carbonyl group.
- MeSH
- Biotransformation MeSH
- Financing, Organized MeSH
- Haemonchus metabolism drug effects MeSH
- Haemonchiasis veterinary MeSH
- Mebendazole analogs & derivatives pharmacokinetics chemistry MeSH
- Sheep Diseases parasitology MeSH
- Sheep MeSH
- Oxidoreductases metabolism MeSH
- Subcellular Fractions MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
Flubendazole (FLU) is a widely used anthelmintic drug belonging to benzimidazole group. Recently, several studies have been published demonstrating its potential to inhibit growth of various tumor cells including those derived from colorectal cancer, breast cancer or leukemia via several mechanisms. In the present study we have investigated cytotoxic effects of FLU on malignant melanoma using A-375, BOWES and RPMI-7951 cell lines representing diverse melanoma molecular types. In all three cell lines, FLU inhibited cell growth and proliferation and disrupted microtubule structure and function which was accompanied by dramatic changes in cellular morphology. In addition, FLU-treated cells accumulated at the G2/M phase of cell cycle and displayed the features of mitotic catastrophe characterized by formation of giant cells with multiple nuclei, abnormal spindles and subsequent apoptotic demise. Although this endpoint was observed in all treated melanoma lines, our analyses showed different activated biochemical signaling in particular cells, thus suggesting a promising treatment potential of FLU in malignant melanoma warranting its further testing.
OBJECTIVES: Flubendazole (FLU), a member of benzimidazole family of anthelmintic drugs, is able to inhibit proliferation of various cancer cells. The aim of present study was to elucidate the mechanisms of antiproliferative effect of FLU on colorectal cancer cells in vitro. METHODS: The effect of FLU on proliferation, microtubular network, DNA content, caspase activation and senescence induction was studied in SW480 and SW620 cell lines. KEY FINDINGS: Flubendazole significantly affected cell proliferation in a pattern typical for mitotic inhibitor. This was accompanied by decrease in cyclin D1 levels, increase in cyclin B1 levels, activation of caspase 2 and caspase 3/7 and PARP cleavage. Morphological observations revealed disruption of microtubular network, irregular mitotic spindles, formation of giant multinucleated cells and increase in nuclear area and DNA content. In SW620 cell line, 37.5% giant multinucleated cells induced by FLU treatment showed positivity for SA-β-galactosidase staining. Cell lines were able to recover from the treatment and this process was faster in SW480 cells. CONCLUSION: Flubendazole in low concentration temporarily inhibits cell proliferation and induces mitotic catastrophe and premature senescence in human colon cancer cells in vitro.
- MeSH
- Spindle Apparatus drug effects ultrastructure MeSH
- Humans MeSH
- Mebendazole analogs & derivatives pharmacology MeSH
- Microtubules drug effects ultrastructure MeSH
- Mitosis drug effects MeSH
- Cell Line, Tumor MeSH
- Giant Cells drug effects ultrastructure MeSH
- Cell Proliferation drug effects MeSH
- Cellular Senescence drug effects MeSH
- Tubulin metabolism MeSH
- Cell Nucleus Size drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Publication type
- Meeting Abstract MeSH
Benzimidazole anthelmintics flubendazole and mebendazole are microtubule-targeting drugs that showed considerable anti-cancer activity in different preclinical models. In this study, the effects of flubendazole and mebendazole on proliferation, migration and cadherin switching were studied in a panel of oral cell lines in vitro. Both compounds reduced the viability of the PE/CA-PJ15 and H376 oral squamous carcinoma cells and of the premalignant oral keratinocytes DOK with the IC50 values in the range of 0.19-0.26 μM. Normal oral keratinocytes and normal gingival fibroblasts were less sensitive to the treatment. Flubendazole and mebendazole also reduced the migration of the PE/CA-PJ15 cell in concentrations that had no anti-migratory effects on the normal gingival fibroblasts. Levels of the focal adhesion kinase FAK, Rho-A and Rac1 GTPases and the Rho guanine nucleotide exchange factor GEF-H1 were decreased in both PE/CA-PJ15 cells and gingival fibroblasts following treatment. Both drugs also interfered with cadherin switching in the model of TGF-β-induced epithelial to mesenchymal transition (EMT) in the DOK cell line. Levels of N-cadherin were reduced in the TGF-β induced cells co-treated with flubendazol and mebendazole in very low concentration (50 nM). These results suggest direct effects of both benzimidazoles on selected processes of EMT in oral cell lines such as cadherin switching as well as cellular migration.
- MeSH
- Cell Line MeSH
- cdc42 GTP-Binding Protein metabolism MeSH
- Epithelial-Mesenchymal Transition drug effects MeSH
- Focal Adhesion Kinase 1 metabolism MeSH
- Cadherins metabolism MeSH
- Humans MeSH
- Mebendazole analogs & derivatives pharmacology MeSH
- Mouth Neoplasms metabolism pathology MeSH
- Cell Movement drug effects MeSH
- Cell Proliferation drug effects MeSH
- rhoA GTP-Binding Protein metabolism MeSH
- Carcinoma, Squamous Cell metabolism pathology MeSH
- Transforming Growth Factor beta pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Fenbendazole (FEN) and flubendazole (FLU) are benzimidazole anthelmintics often used in pig management for the control of nematodoses. The in vivo study presented here was designed to test the influence of FLU and FEN on cytochrome P4501A and other cytochrome P450 (CYP) isoforms, UDP-glucuronosyl transferase and several carbonyl reducing enzymes. The results indicated that FEN (in a single therapeutic dose as well as in repeated therapeutic doses) caused significant induction of pig CYP1A, while FLU did not show an inductive effect towards this isoform. Some of the other hepatic and intestinal biotransformation enzymes that were assayed were moderately influenced by FEN or FLU. Strong CYP1A induction following FEN therapy in pigs may negatively affect the efficacy and pharmacokinetics of FEN itself or other simultaneously or consecutively administered drugs. From the perspective of biotransformation enzyme modulation, FLU would appear to be a more convenient anthelmintic therapy of pigs than FEN.
- MeSH
- Alcohol Oxidoreductases metabolism MeSH
- Anthelmintics pharmacology MeSH
- Fenbendazole pharmacology MeSH
- Financing, Organized MeSH
- Glucuronosyltransferase metabolism MeSH
- Isoenzymes MeSH
- Microsomes, Liver enzymology metabolism drug effects MeSH
- Mebendazole analogs & derivatives pharmacology MeSH
- Swine Diseases enzymology drug therapy parasitology MeSH
- Intestinal Diseases, Parasitic enzymology drug therapy veterinary MeSH
- Swine MeSH
- Steroid Hydroxylases metabolism MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- Intestine, Small enzymology metabolism drug effects MeSH
- Blotting, Western veterinary MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
The aim of this project was to study the influence of haemonchosis, a common parasitic infection of small ruminants caused by Haemonchus contortus, on the activity of biotransformation enzymes and on in vitro flubendazole (FLU) biotransformation in liver and small intestine of lambs (Ovis aries). Twelve lambs were divided into three groups: non-infected animals, animals orally infected with larvae of H. contortus ISE strain for 7 weeks and for 11 weeks. At the end of the experiment, hepatic and intestinal subcellular fractions were prepared and used for assays of biotransformation enzymes activities and FLU metabolism testing. The activities of hepatic cytochromes P450, flavine monooxygenases and carbonyl-reducing enzymes were decreased in infected animals. UDP-glucuronosyl transferase activity was significantly lower (by 35%) in 11 weeks infected animals than that in control animals. When in vitro metabolism of FLU was compared in control and infected animals, significantly lower velocity of FLU reduction was found in infected animals. Slower FLU reduction may be beneficial for the haemonchosis treatment using FLU, because FLU will remain longer in the organism and could cause longer contact of parasites with FLU.
- MeSH
- Biotransformation MeSH
- Haemonchus drug effects MeSH
- Haemonchiasis drug therapy metabolism veterinary MeSH
- Liver enzymology metabolism MeSH
- Mebendazole analogs & derivatives metabolism therapeutic use MeSH
- Sheep Diseases metabolism MeSH
- Sheep MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Controlled Clinical Trial MeSH
- Research Support, Non-U.S. Gov't MeSH
Drug entry into the body of a helminth is a key factor in the efficacy of anthelmintics. The present project was designed to study the ex vivo uptake and efflux of the benzimidazole anthelmintic flubendazole (FLU) in four strains of H. contortus: the ISE strain (fully susceptible to anthelmintics), the ISE-S strain (resistant to ivermectin), the BR strain (resistant to benzimidazoles) and the WR strain (multi-resistant). The transport of FLU between dead and living nematodes was also compared as well as the effect of verapamil, an inhibitor of the main efflux ABCB1 transporter (P-glycoprotein), on FLU accumulation in nematodes. The obtained results showed that FLU is able to effectively enter H. contortus adults due to high FLU lipophilicity. Passive diffusion is probably the only mechanism in both FLU import and efflux from nematodes. No differences in FLU transport were found among four H. contortus strains with different sensitivity to anthelmintics. No active FLU efflux from H. contortus and no effect of verapamil were observed, indicating that H. contortus cannot protect itself against FLU by the active removal of this anthelmintic from its body.
- MeSH
- Anthelmintics metabolism pharmacokinetics pharmacology MeSH
- Haemonchus drug effects MeSH
- Drug Resistance MeSH
- Drug Interactions MeSH
- Mebendazole analogs & derivatives metabolism pharmacokinetics pharmacology MeSH
- Organic Anion Transporters antagonists & inhibitors MeSH
- Verapamil pharmacokinetics MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
