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.

• Klíčová slova
• Flubendazole, Melanoma, Microtubules, Mitotic catastrophe, apoptosis,
• MeSH
• antinematodní látky toxicita   MeSH
• apoptóza účinky léků   MeSH
• lidé MeSH
• mebendazol analogy a deriváty   toxicita   MeSH
• melanom * MeSH
• mitóza účinky léků   MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antinematodní látky MeSH
• flubendazole MeSH Prohlížeč
• mebendazol MeSH

Glioblastoma multiforme (GBM) represents approximately 60% of all brain tumors in adults. This malignancy shows a high biological and genetic heterogeneity associated with exceptional aggressiveness, leading to a poor survival of patients. This review provides a summary of the basic biology of GBM cells with emphasis on cell cycle and cytoskeletal apparatus of these cells, in particular microtubules. Their involvement in the important oncosuppressive process called mitotic catastrophe will next be discussed along with select examples of microtubule-targeting agents, which are currently explored in this respect such as benzimidazole carbamate compounds. Select microtubule-targeting agents, in particular benzimidazole carbamates, induce G2/M cell cycle arrest and mitotic catastrophe in tumor cells including GBM, resulting in phenotypically variable cell fates such as mitotic death or mitotic slippage with subsequent cell demise or permanent arrest leading to senescence. Their effect is coupled with low toxicity in normal cells and not developed chemoresistance. Given the lack of efficient cytostatics or modern molecular target-specific compounds in the treatment of GBM, drugs inducing mitotic catastrophe might offer a new, efficient alternative to the existing clinical management of this at present incurable malignancy.

• Klíčová slova
• benzimidazole carbamates, cell death, glioblastoma multiforme, microtubule-targeting agents, mitotic catastrophe,
• MeSH
• glioblastom * metabolismus   mortalita   terapie   MeSH
• kontrolní body fáze G2 buněčného cyklu * MeSH
• kontrolní body M fáze buněčného cyklu * MeSH
• lidé MeSH
• mitóza * MeSH
• nádory mozku * metabolismus   mortalita   patologie   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

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.

• Klíčová slova
• benzimidazoles, colorectal cancer cells, flubendazole, mitotic catastrophe, senescence,
• MeSH
• aparát dělícího vřeténka účinky léků   ultrastruktura   MeSH
• lidé MeSH
• mebendazol analogy a deriváty   farmakologie   MeSH
• mikrotubuly účinky léků   ultrastruktura   MeSH
• mitóza účinky léků   MeSH
• nádorové buněčné linie MeSH
• obrovské buňky účinky léků   ultrastruktura   MeSH
• proliferace buněk účinky léků   MeSH
• stárnutí buněk účinky léků   MeSH
• tubulin metabolismus   MeSH
• velikost buněčného jádra účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• flubendazole MeSH Prohlížeč
• mebendazol MeSH
• tubulin MeSH

Mitotic catastrophe induced by mictotubule-targeting drugs such as benzimidazole carbamates has been demonstrated to be an efficient mechanism for suppression of tumor cells growth and proliferation, with variable resulting endpoints. The present study was designed to explore some of these endpoints; i.e. the apoptosis as well as autophagy and their related signaling in several stabilized cell lines as well as human explant melanoma cells treated with flubendazole (FLU). FLU-induced mitotic catastrophe resulted in mitochondrial and caspase-dependent apoptosis, which occurred at various rates in all treated cells during 96 h of treatment. The process was characterized by enhanced transcriptional activity of TP53 and NF-κB as well as upregulated Noxa expression. Also, inactivation of Bcl-2, BclXL and Mcl-1 proteins by JNK mediated phosphorylation was observed. Although increased autophagic activity took place in treated cells too, no discernible functional linkage with ongoing cell death process was evidenced. Together these results advance our evidence over the effectiveness of FLU cytotoxicity-related killing of melanoma cells while calling for more extensive testing of melanoma samples as a prerequisite of further preclinical evaluation of FLU antineoplastic potential.

• Klíčová slova
• Apoptosis, Autophagy, Flubendazole, Melanoma, Mitotic catastrophe, Necrosis,
• MeSH
• apoptóza účinky léků   MeSH
• autofagie účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• cytochromy c metabolismus   MeSH
• JNK mitogenem aktivované proteinkinasy metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mebendazol analogy a deriváty   farmakologie   MeSH
• melanom farmakoterapie   metabolismus   MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• mitóza MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• protein MCL-1 metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BCL2 protein, human MeSH Prohlížeč
• cytochromy c MeSH
• flubendazole MeSH Prohlížeč
• JNK mitogenem aktivované proteinkinasy MeSH
• MCL1 protein, human MeSH Prohlížeč
• mebendazol MeSH
• nádorový supresorový protein p53 MeSH
• protein MCL-1 MeSH
• protinádorové látky MeSH
• protoonkogenní proteiny c-bcl-2 MeSH

As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.

• Klíčová slova
• MU380, castration-resistant prostate cancer, checkpoint kinase 1, docetaxel resistance, gemcitabine, mitotic catastrophe,
• MeSH
• buněčná smrt účinky léků   MeSH
• checkpoint kinasa 1 antagonisté a inhibitory   metabolismus   MeSH
• chemorezistence účinky léků   MeSH
• deoxycytidin analogy a deriváty   farmakologie   MeSH
• docetaxel farmakologie   MeSH
• gemcitabin MeSH
• lidé MeSH
• mitóza * účinky léků   MeSH
• myši SCID MeSH
• nádorové buněčné linie MeSH
• nádory prostaty patologie   MeSH
• piperidiny chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• pyrazoly chemie   farmakologie   MeSH
• pyrimidiny chemie   farmakologie   MeSH
• S fáze účinky léků   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• checkpoint kinasa 1 MeSH
• CHEK1 protein, human MeSH Prohlížeč
• deoxycytidin MeSH
• docetaxel MeSH
• gemcitabin MeSH
• MU380 MeSH Prohlížeč
• piperidiny MeSH
• pyrazoly MeSH
• pyrimidiny MeSH

Abdominal catastrophe is a serious clinical condition, usually being a complication arising during treatment of intraabdominal nontraumatic disorders or abdominal injuries. Most commonly, inflamation- secondary peritonitis, is concerned. Abdominal catastrophe also includes secondary signs of sepsis, abdominal compartment syndrome and enterocutaneous fistules. Most septic abdominal disorders which show signs of abdominal catastrophy, require surgical intervention and reinterventions--planned or "on demand" laparotomies. During the postoperative period, the patient requires intensive care management, including steps taken to stabilize his/hers condition, management of sepsis and metabolic and nutritional support measures, as well as adequate indication for reoperations. New technologies aimed at prevention of complications in laparostomies and to improve conditions for final laparotomy closure are used in phase procedures for surgical management of intraabdominal infections. Despite the new technologies, abdominal catastrophe has higher morbidity and lethality risk rates.

• MeSH
• akutní bolest břicha etiologie   chirurgie   MeSH
• kompartment syndrom epidemiologie   chirurgie   MeSH
• laparotomie MeSH
• lidé MeSH
• peritonitida etiologie   chirurgie   MeSH
• reoperace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH

Photodynamic therapy (PDT) is a useful tool against cancer and various other diseases. PDT is capable to induce different cell death mechanisms, due to the PDT evoked reactive oxygen species (ROS) production and is dose dependent. It is known that cytoskeleton is responsible for numerous cell functions, including cell division, maintenance of cell shape, their adhesion ability and movement. PDT initiated redistribution and subsequent disintegration of cytoskeletal components that precedes cell death. Here was present our results in HeLa and G361 cells subjected to sublethal PDT treatments using α,β,χ,δ porphyrin-Tetrakis (1-methylpyridinium-4-yl) p-Toluenesulfonate porphyrin (TMPyP). The photosensitizer (PS) induced transient increasing of mitotic index (MI) observable early after PDT, cell cycle arrest, microtubule (MTs) disorganization of interphase cells, aberrant mitosis and formation of rounded cells with partial loss of adherence. Some cells were partly resistant to PDT induced MTs disorganization. The differences between both cell lines to PDT response were described. This is the first evidence of TMPyP - PDT induced microtubule disorganization and the cell death mechanisms known as mitotic catastrophe and the first detail analysis of microtubule aberrations of mitotic and interphase cells in HeLa and G361 cell lines. New modification of techniques of protein immunolabeling was developed.

• Klíčová slova
• Aberrant mitosis, Cell cycle analysis, Fluorescent immunodetection, Multipolar spindle, PDT resistance,
• MeSH
• cytoskelet účinky léků   metabolismus   MeSH
• fluorescenční mikroskopie MeSH
• fotochemoterapie MeSH
• fotosenzibilizující látky farmakologie   terapeutické užití   MeSH
• HeLa buňky MeSH
• histony metabolismus   MeSH
• kontrolní body buněčného cyklu účinky léků   účinky záření   MeSH
• lidé MeSH
• mikrotubuly chemie   metabolismus   MeSH
• mitóza účinky léků   účinky záření   MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   MeSH
• porfyriny farmakologie   terapeutické užití   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• světlo MeSH
• viabilita buněk účinky léků   účinky záření   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fotosenzibilizující látky MeSH
• histony MeSH
• porfyriny MeSH
• reaktivní formy kyslíku MeSH
• tetra(4-N-methylpyridyl)porphine MeSH Prohlížeč

It has been 36 years since the Chernobyl Nuclear Power Plant catastrophe, but the consumption of wild mushrooms in Ukrainian Polissya is still dangerous since its territory is heavily contaminated by radionuclides. The aim of this study was to estimate 137Cs and 90Sr uptake in wild mushrooms from locations with contrast radioactive loads (Zhytomyr Polissya, Ukraine). In mushroom samples collected from Drevlyanskyi Nature Reserve since 2013 (average levels of soil surface contamination with 137Cs are 555-1480 kBq m-2), the highest levels of 137Cs were observed in symbiotroph species - Imleria badia (≤ 2680 kBq kg-1 dry mass [dm]), Tricholoma equestre (≤ 1420 kBq kg-1 dm), Lactarius rufus (≤ 602 kBq kg-1 dm), Sarcodon imbricatus (≤ 464 kBq kg-1 dm), Leccinum scabrum (≤ 117 kBq kg-1 dm), Suillus bovinus (≤ 118 kBq kg-1 dm), and Boletus edulis (≤ 96 kBq kg-1 dm). 90Sr activity was significantly lower, with the highest levels detected in Russula emetica (193 Bq kg-1 dm), Daedaleopsis confragosa (145 Bq kg-1 dm), and Hypholoma fasciculare (141 Bq kg-1 dm). The 137Cs/90Sr ratio in fruiting bodies in samples ranged from 6.1 (Bovistella utriformis) to 28,979 (T. equestre). Activity concentrations in mushrooms from locations with relatively low contamination with 137Cs (18.5-27.75 kBq m-2) also reached the highest values in symbiotroph species I. badia (7698 Bq kg-1 dm), Lactarius vellereus (6072 Bq kg-1 dm), and S. luteus (1448 Bq kg-1 dm). Potential calculated annual effective doses due to mushroom consumption by adults, considering only the effect of 137Cs, reached 0.311 and 8.71 mSv in B. edulis and I. badia from highly contaminated locations, respectively, and 0.0014 and 0.009 mSv in these species from low contaminated ones.

• MeSH
• Agaricales * MeSH
• černobylská havárie * MeSH
• dospělí MeSH
• jaderné elektrárny MeSH
• lidé MeSH
• radioaktivní látky znečišťující půdu * analýza   MeSH
• radioizotopy cesia MeSH
• radioizotopy stroncia MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Ukrajina MeSH
• Názvy látek
• Cesium-137 MeSH Prohlížeč
• radioaktivní látky znečišťující půdu * MeSH
• radioizotopy cesia MeSH
• radioizotopy stroncia MeSH
• Strontium-90 MeSH Prohlížeč

Three airplanes were involved in an airshow accident at the Ramstein military airbase on 28th of August 1988 causing immediate 45 dead and approximate 400 injured people. As a Level I Trauma facility we received 47 patients in different state of distress direct from airfield within an hour. The disaster plan was activated and sufficient personal and infrastructure could be mobilized.

• MeSH
• časové faktory MeSH
• lidé MeSH
• náhlé příhody MeSH
• nehody letecké * MeSH
• péče o pacienty v kritickém stavu * MeSH
• plánování postupu v případě katastrof * MeSH
• popálení terapie   MeSH
• rány a poranění terapie   MeSH
• traumatologická centra MeSH
• třídění pacientů organizace a řízení   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Mitosis is a crucial stage in the cell cycle, controlled by a vast network of regulators responding to multiple internal and external factors. The fission yeast Schizosaccharomyces pombe demonstrates catastrophic mitotic phenotypes due to mutations or drug treatments. One of the factors provoking catastrophic mitosis is a disturbed lipid metabolism, resulting from, for example, mutations in the acetyl-CoA/biotin carboxylase (cut6), fatty acid synthase (fas2, also known as lsd1) or transcriptional regulator of lipid metabolism (cbf11) genes, as well as treatment with inhibitors of fatty acid synthesis. It has been previously shown that mitotic fidelity in lipid metabolism mutants can be partially rescued by ammonium chloride supplementation. In this study, we demonstrate that mitotic fidelity can be improved by multiple nitrogen sources. Moreover, this improvement is not limited to lipid metabolism disturbances but also applies to a number of unrelated mitotic mutants. Interestingly, the partial rescue is not achieved by restoring the lipid metabolism state, but rather indirectly. Our results highlight a novel role for nitrogen availability in mitotic fidelity.

• Klíčová slova
• Closed mitosis, Cut, Lipid metabolism, Mitotic catastrophe, Nitrogen availability, TOR,
• MeSH
• dusík * metabolismus   MeSH
• metabolismus lipidů * MeSH
• mitóza * MeSH
• mutace genetika   MeSH
• Schizosaccharomyces pombe - proteiny * metabolismus   genetika   MeSH
• Schizosaccharomyces * metabolismus   genetika   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dusík * MeSH
• Schizosaccharomyces pombe - proteiny * MeSH