benzimidazole carbamate Dotaz Zobrazit nápovědu
- MeSH
- benomyl toxicita MeSH
- benzimidazoly toxicita MeSH
- dusitany MeSH
- experimentální nádory chemicky indukované MeSH
- fungicidy průmyslové toxicita MeSH
- karbamáty toxicita MeSH
- myši MeSH
- nádory brzlíku chemicky indukované MeSH
- nehodgkinský lymfom chemicky indukované MeSH
- nitrosaminy metabolismus toxicita MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
Benzimidazoles anthelmintics, which enter into environment primarily through excretion in the feces or urine of treated animals, can affect various organisms and disrupt ecosystem balance. The present study was designed to test the phytotoxicity and biotransformation of the three benzimidazole anthelmintics albendazole (ABZ), fenbendazole (FBZ) and flubendazole (FLU) in the harebell (Campanula rotundifolia). This meadow plant commonly grows in pastures and comes into contact with anthelmintics through the excrements of treated animals. Suspensions of harebell cells in culture medium were used as an in vitro model system. ABZ, FLU and FBZ were not found to be toxic for harebell cells, which were able to metabolize ABZ, FLU and FBZ via the formation of a wide scale of metabolites. Ultrahigh-performance liquid chromatography coupled with high mass accuracy tandem mass spectrometry (UHPLC-MS/MS) led to the identification of 24, 18 and 29 metabolites of ABZ, FLU and FBZ, respectively. Several novel metabolites were identified for the first time. Based on the obtained results, the schemes of the metabolic pathways of these anthelmintics were proposed. Most of these metabolites can be considered deactivation products, but a substantial portion of them may readily be decomposed to biologically active substances which could negatively affect ecosystems.
- MeSH
- albendazol metabolismus MeSH
- anthelmintika chemie metabolismus MeSH
- benzimidazoly chemie metabolismus MeSH
- biotransformace MeSH
- Campanulaceae cytologie metabolismus MeSH
- ekosystém MeSH
- feces chemie MeSH
- fenbendazol metabolismus MeSH
- kultivované buňky MeSH
- mebendazol analogy a deriváty metabolismus MeSH
- metabolické sítě a dráhy * MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Benzimidazole anthelmintics, the drugs against parasitic worms, are widely used in human as well as veterinary medicine. Following excretion, these substances may persist in the environment and impact non-target organisms. In order to test phytoremediation as a possible tool for detoxification of anthelmintics in environment, the biotransformation pathways of albendazole (ABZ) and flubendazole (FLU) were studied in reed (Phragmites australis) in vitro. Reed cells were able to uptake and biotransform both anthelmintics. Ten ABZ metabolites and five FLU metabolites were found. Some atypical biotransformation reactions (formation of glucosylglucosides, acetylglucosides and xylosylglucosides), which have not been described previously, were identified. Based on the obtained results, the schemes of metabolic pathways of ABZ and FLU in reed were proposed. Most of ABZ and FLU metabolites can be considered as anthelmintically less active; therefore uptake and biotransformation of these anthelmintics by reed could be useful for decrease of their toxicity in environment.
- MeSH
- albendazol chemie metabolismus MeSH
- anthelmintika chemie metabolismus MeSH
- benzimidazoly chemie metabolismus MeSH
- biodegradace MeSH
- biotransformace MeSH
- lidé MeSH
- lipnicovité cytologie metabolismus MeSH
- mebendazol analogy a deriváty chemie metabolismus MeSH
- metabolická inaktivace * MeSH
- metabolické sítě a dráhy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This study aimed to test the antiproliferative effect of three benzimidazole anthelmintics in intestinal cancer cells and to investigate whether these drugs, which inhibit tubulin polymerization, can potentiate the efficacy of the microtubule-stabilizing drug paclitaxel (PTX). Four intestinal cancer cell lines, SW480, SW620, HCT8, and Caco2, with different origins and growth characteristics were used. The antiproliferative effect of albendazole (ABZ), ricobendazole (RBZ), flubendazole (FLU), and their combinations with PTX was tested using three different end-point viability assays, cell cycle distribution analysis, and the x-CELLigence System for real-time cell analysis. ABZ and FLU inhibited cell proliferation significantly in a concentration-dependent and time-dependent manner through cell arrest in the G2/M phase. RBZ was not effective at any concentration tested. The cell lines differed in sensitivity to FLU and ABZ, with HCT8 being the most sensitive, showing IC₅₀ values for ABZ and FLU that reached 0.3 and 0.9 μmol/l, respectively. Combinations of PTX+ABZ and PTX+FLU decreased cell viability more effectively when compared with treatment with individual drugs alone. The anthelmintic benzimidazole drugs ABZ and FLU show a significant cytostatic effect and potentiate the efficacy of PTX in intestinal cancer cells.
- MeSH
- adenokarcinom farmakoterapie MeSH
- albendazol analogy a deriváty farmakologie MeSH
- anthelmintika farmakologie MeSH
- antitumorózní látky fytogenní farmakologie MeSH
- antitumorózní látky farmakologie MeSH
- chemorezistence účinky léků MeSH
- G2 fáze účinky léků MeSH
- inhibiční koncentrace 50 MeSH
- lidé MeSH
- mebendazol analogy a deriváty farmakologie MeSH
- mikrotubuly účinky léků MeSH
- modulátory tubulinu farmakologie MeSH
- nádorové buněčné linie MeSH
- paclitaxel farmakologie MeSH
- proliferace buněk účinky léků MeSH
- stabilita proteinů účinky léků MeSH
- střevní nádory farmakoterapie MeSH
- synergismus léků MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Methyl benzimidazole carbamate fungicides, including benomyl, are widely used in agriculture, and to eliminate entomopathogenic infections. We treated queens of Myrmica rubra (Hymenoptera:Formicidae) infected or not by Rickia wasmannii (Laboulbeniales:Laboulbeniaceae) with benomyl, 1mg/ml p.o. for six weeks. Benomyl did not treat the infection, and the treatment alone caused strong decrease in the fecundity of control healthy queens from 18.0±8.4 to 3.7±5.2eggs per healthy queen. This is the first evidence on severe adverse effects of methyl benzimidazole carbamate fungicide on the fecundity of insects, which might be responsible for altered species composition of ant assemblages in the cultural landscape.
- MeSH
- benomyl toxicita MeSH
- fertilita účinky léků MeSH
- Formicidae účinky léků parazitologie MeSH
- fungicidy průmyslové toxicita MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Tumor suppressor p53 is mutated in about 50% of cancers. Most malignant melanomas carry wild-type p53, but p53 activity is often inhibited due to overexpression of its negative regulators Mdm2 or MdmX. We performed high throughput screening of 2448 compounds on A375 cells carrying p53 activity luciferase reporter construct to reveal compounds that promote p53 activity in melanoma. Albendazole and fenbendazole, two approved and commonly used benzimidazole anthelmintics, stimulated p53 activity and were selected for further studies. The protein levels of p53 and p21 increased upon the treatment with albendazole and fenbendazole, indicating activation of the p53-p21 pathway, while the levels of Mdm2 and MdmX decreased in melanoma and breast cancer cells overexpressing these proteins. We also observed a reduction of cell viability and changes of cellular morphology corresponding to mitotic catastrophe, i.e., G2/M cell cycle arrest of large multinucleated cells with disrupted microtubules. In summary, we established a new tool for testing the impact of small molecule compounds on the activity of p53 and used it to identify the action of benzimidazoles in melanoma cells. The drugs promoted the stability and transcriptional activity of wild-type p53 via downregulation of its negative regulators Mdm2 and MdmX in cells overexpressing these proteins. The results indicate the potential for repurposing the benzimidazole anthelmintics for the treatment of cancers overexpressing p53 negative regulators.
- MeSH
- albendazol farmakologie MeSH
- benzimidazoly farmakologie MeSH
- down regulace MeSH
- fenbendazol farmakologie MeSH
- jaderné proteiny metabolismus MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- melanom farmakoterapie metabolismus MeSH
- MFC-7 buňky MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- přehodnocení terapeutických indikací léčivého přípravku MeSH
- proliferace buněk účinky léků MeSH
- proteiny buněčného cyklu MeSH
- protoonkogenní proteiny c-mdm2 metabolismus MeSH
- protoonkogenní proteiny metabolismus MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- rychlé screeningové testy MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- albendazol aplikace a dávkování MeSH
- benzimidazoly aplikace a dávkování MeSH
- diethylkarbamazin aplikace a dávkování MeSH
- lidé MeSH
- mebendazol aplikace a dávkování MeSH
- thiabendazol aplikace a dávkování MeSH
- Toxocara růst a vývoj MeSH
- toxokaróza diagnóza epidemiologie prevence a kontrola MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
V terénu výrazně molekulárně-geneticky heterogenního nemalobuněčného plicního karcinomu představuje mutace genu BRAF potenciální biomarker pro cílenou protinádorovou léčbu. Cílem studie PHAROS bylo zhodnotit účinnost a bezpečnost kombinované léčby enkorafenibem a binimetinibem u pacientů s metastatickým NSCLC a mutací BRAF V600. Klinická studie dokumentovala četnost léčebných odpovědí dle nezávislého radiologického hodnocení 75 % u nepředléčených pacientů, resp. 46 % u předléčených pacientů, a to s přiměřenou toxicitou.
In non-small cell lung cancer, characterized by molecular-genetic heterogeneity, a mutation in the BRAF gene represents a potential biomarker for targeted antitumour therapy. The aim of the PHAROS study was to evaluate the efficacy and safety of combined treatment with encorafenib and binimetinib in patients with metastatic NSCLC harbouring a the BRAF V600 mutation. The clinical study met its primary objective showing an overall response rate according to the independent radiological review of 75% in treatment-naive and 46% in previously treated patients, with manageable toxicity.
