• MeSH
• buněčný cyklus fyziologie   MeSH
• proteiny buněčného cyklu fyziologie   MeSH
• Publikační typ
• monografie MeSH

• Konspekt
• Buněčná biologie. Cytologie
• NLK Obory
• biochemie
• biologie

Glioblastoma multiforme (GBM) belongs to most aggressive and invasive primary brain tumor in adults whose prognosis and survival remains poor. Potential new treatment modalities include targeting the cytoskeleton. In our study, we demonstrated that repurposed drug flubendazole (FLU) significantly inhibits proliferation and survival of GBM cells. FLU exerted its effect by affecting microtubule structure and our results also suggest that FLU influences tubulins expression to a certain degree. Moreover, FLU effects decreased activation of STAT3 and also partially inhibited its expression, leading to upregulation of p53 signaling pathway and subsequent cell cycle arrest at G2/M phase as well as caspase-dependent cell death in GBM cells. These results suggest FLU as a promising agent to be used in GBM treatment and prompting further testing of its effects on GBM.

• MeSH
• apoptóza MeSH
• buněčný cyklus MeSH
• dospělí MeSH
• glioblastom * patologie   MeSH
• kontrolní body buněčného cyklu MeSH
• lidé MeSH
• mebendazol farmakologie   terapeutické užití   MeSH
• nádorové buněčné linie MeSH
• nádory mozku * patologie   MeSH
• proliferace buněk MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The aim of our study was to determine the effect of potential anti-tumour agent benfluron on human leukemic cells MOLT-4 and elucidate the molecular mechanisms of response of tumour cells to this chemotherapeutic agent. It has been shown that the mechanisms of action of benfluron are complex, but the molecular pathways of the cytostatic effect have remained unknown and the present study contributes to their elucidation. In this work, benfluron reduced viability of the treated cells and induced caspase-mediated apoptosis. The programmed cell death was associated with activation of caspases 8, 9 and 3/7. Moreover, exposure of cells to benfluron resulted in accumulation of the cells primarily in late S and G2/M phases. The changes in the levels of key proteins show that benfluron provoked activation of p53 and induced phosphorylation of p53 on serine 15 and serine 392. The application of benfluron led to phosphorylation of Chk1 on serine 345 and phosphorylation of Chk2 on threonine 68 in the treated cells. Higher doses of benfluron caused phosphorylation of ERK1/2 on threonine 202 and tyrosine 204, whereas JNK and p38 kinases were not activated. In conclusion, benfluron induces apoptosis, cell cycle arrest in late S and G2/M phases, and activates various signalling pathways of the DNA damage response.

• MeSH
• apoptóza účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• fluoreny farmakologie   MeSH
• fosforylace účinky léků   MeSH
• G2 fáze účinky léků   MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• leukemie metabolismus   MeSH
• lidé MeSH
• mitogenem aktivovaná proteinkinasa 1 metabolismus   MeSH
• mitogenem aktivovaná proteinkinasa 3 metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Brassinosteroids (BRs) are plant hormones that appear to be ubiquitous in both lower and higher plants. Recently, we published the first evidence that some natural BRs induce cell growth inhibitory responses in several human cancer cell lines without affecting normal non-tumor cell growth (BJ fibroblasts). The aim of the study presented here was to examine the mechanism of the antiproliferative activity of the natural BRs 28-homocastasterone (28-homoCS) and 24-epibrassinolide (24-epiBL) in human hormone-sensitive and -insensitive (MCF-7 and MDA-MB-468, respectively) breast cancer cell lines. The effects of 6, 12 and 24h treatments with 28-homoCS and 24-epiBL on cancer cells were surveyed using flow cytometry, Western blotting, TUNEL assays and immunofluorescence analyses. The studied BRs inhibited cell growth and induced blocks in the G(1) cell cycle phase. ER-α immunoreactivity was uniformly present in the nuclei of control MCF-7 cells, while cytoplasmic speckles of ER-α immunofluorescence appeared in BR-treated cells (IC(50), 24h). ER-β was relocated to the nuclei following 28-homoCS treatment and found predominantly at the periphery of the nuclei in 24-epiBL-treated cells after 24h of treatment. These changes were also accompanied by down-regulation of the ERs following BR treatment. In addition, BR application to breast cancer cells resulted in G(1) phase arrest. Furthermore, TUNEL staining and double staining with propidium iodide and acridine orange demonstrated the BR-mediated induction of apoptosis in both cell lines, although changes in the expression of apoptosis-related proteins were modulated differently by the BRs in each cell line. The studied BRs seem to exert potent growth inhibitory effects via interactions with the cell cycle machinery, and they could be highly valuable leads for agents for managing breast cancer.

• MeSH
• apoptóza účinky léků   MeSH
• brassinosteroidy MeSH
• buněčný cyklus účinky léků   MeSH
• cholestanoly farmakologie   MeSH
• cholestanony farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prsu patologie   MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• steroidy heterocyklické farmakologie   MeSH
• transport proteinů účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Radiotherapy in children causes debilitating cognitive decline, partly linked to impaired neurogenesis. Irradiation targets primarily cancer cells but also endogenous neural stem/progenitor cells (NSPCs) leading to cell death or cell cycle arrest. Here we evaluated the effects of lithium on proliferation, cell cycle and DNA damage after irradiation of young NSPCs in vitro.NSPCs were treated with 1 or 3 mM LiCl and we investigated proliferation capacity (neurosphere volume and bromodeoxyuridine (BrdU) incorporation). Using flow cytometry, we analysed apoptosis (annexin V), cell cycle (propidium iodide) and DNA damage (γH2AX) after irradiation (3.5 Gy) of lithium-treated NSPCs.Lithium increased BrdU incorporation and, dose-dependently, the number of cells in replicative phase as well as neurosphere growth. Irradiation induced cell cycle arrest in G1 and G2/M phases. Treatment with 3 mM LiCl was sufficient to increase NSPCs in S phase, boost neurosphere growth and reduce DNA damage. Lithium did not affect the levels of apoptosis, suggesting that it does not rescue NSPCs committed to apoptosis due to accumulated DNA damage.Lithium is a very promising candidate for protection of the juvenile brain from radiotherapy and for its potential to thereby improve the quality of life for those children who survive their cancer.

• MeSH
• apoptóza účinky léků   účinky záření   MeSH
• chlorid lithný aplikace a dávkování   farmakologie   MeSH
• hipokampus cytologie   účinky léků   účinky záření   MeSH
• kontrolní body buněčného cyklu účinky léků   účinky záření   MeSH
• kultivované buňky MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nervové kmenové buňky cytologie   účinky léků   účinky záření   MeSH
• neurogeneze účinky léků   fyziologie   účinky záření   MeSH
• novorozená zvířata MeSH
• poškození DNA účinky léků   účinky záření   MeSH
• proliferace buněk účinky léků   účinky záření   MeSH
• průtoková cytometrie MeSH
• radioizotopy kobaltu MeSH
• techniky in vitro MeSH
• záření gama MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cell cycle represents not only a tightly orchestrated mechanism of cell replication and cell division but it also plays an important role in regulation of cell fate decision. Particularly in the context of pluripotent stem cells or multipotent progenitor cells, regulation of cell fate decision is of paramount importance. It has been shown that human embryonic stem cells (hESCs) show unique cell cycle characteristics, such as short doubling time due to abbreviated G1 phase; these properties change with the onset of differentiation. This review summarizes the current understanding of cell cycle regulation in hESCs. We discuss cell cycle properties as well as regulatory machinery governing cell cycle progression of undifferentiated hESCs. Additionally, we provide evidence that long-term culture of hESCs is accompanied by changes in cell cycle properties as well as configuration of several cell cycle regulatory molecules.

• MeSH
• buněčná diferenciace MeSH
• buněčné kultury MeSH
• buněčný cyklus fyziologie   MeSH
• embryonální kmenové buňky cytologie   fyziologie   MeSH
• kontrolní body buněčného cyklu fyziologie   MeSH
• lidé MeSH
• pluripotentní kmenové buňky cytologie   fyziologie   MeSH
• proteiny buněčného cyklu metabolismus   fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

OBJECTIVES: This study was performed to explore the strategy of combining Chk1 inhibitors with ionizing radiation (IR) to selectively target p53-deficient cancer cells. MATERIALS AND METHODS: Survival and cell cycle progression were measured in response to IR and the Chk1 inhibitors, UCN-01 and CEP-3891, in colon carcinoma HCT116 p53+/+ and p53-/- cells, and in osteosarcoma U2OS-VP16 cells with conditional expression of dominant-negative p53 (p53DD). RESULTS: Clonogenic survival was selectively reduced in HCT116 p53-/- compared to p53+/+ cells after treatment with UCN-01 and IR, and HCT116 p53+/+ cells also displayed strong p53-dependent G(1) arrest in the 1st cell cycle after IR. In contrast, clonogenic survival was affected similarly in U2OS-VP16 cells with and without expression of p53DD. However, death of U2OS-VP16 cells was p53 dependent as assessed by cell viability assay at 72 h, and this was associated with p53-dependent G(1) arrest in the 2nd cell cycle after treatment. Notably, HCT116 cells were overall more resistant than U2OS cells to cytotoxic effects of Chk1 inhibitors. CONCLUSION: Our results suggest that p53-dependent G(1) arrest in both 1st and 2nd cell cycles may protect human cancer cells from cell death after treatment with IR and Chk1 inhibitors. However, a challenge for future clinical use will be that different cancers display different intrinsic sensitivity to such inhibitors.

• MeSH
• buněčná smrt účinky léků   genetika   MeSH
• buněčný cyklus * účinky léků   genetika   účinky záření   MeSH
• geny p53 účinky léků   MeSH
• HCT116 buňky MeSH
• ionizující záření MeSH
• lidé MeSH
• nádorový supresorový protein p53 * genetika   metabolismus   fyziologie   MeSH
• nádory nervového systému genetika   MeSH
• nádory tračníku * farmakoterapie   genetika   metabolismus   MeSH
• nádory * genetika   MeSH
• proteinkinasy MeSH
• staurosporin analogy a deriváty   MeSH
• viabilita buněk účinky léků   genetika   účinky záření   MeSH
• Check Tag
• lidé MeSH

PTEN, a tumor suppressor commonly targeted in human cancer, possesses phosphatase activities toward both protein and lipid substrates. While PTEN suppresses gliomas through cell cycle inhibition which requires its lipid phosphatase activity, PTEN's effects on other tumor types and the role of its protein phosphatase activity are controversial or unknown. Here we show that exogenous wild-type PTEN arrests some, but not all human breast cancer cell lines in G1, in a manner independent of endogenous PTEN. Unexpectedly, the G129E mutant of PTEN selectively deficient in the lipid phosphatase activity still blocked the cell cycle of MCF-7 cells, while the G129R and H123Y mutants lacking both phosphatase activities were ineffective. These results suggest that PTEN's protein phosphatase activity likely contributes to its tumor suppressor function in subsets of tumors and that elucidation of downstream targets which dictate cellular responses to PTEN may have important implications for future cancer treatment strategies. Copyright 2000 Academic Press.

• MeSH
• buněčný cyklus MeSH
• elektroforéza v polyakrylamidovém gelu MeSH
• fosfatasy fyziologie   genetika   MeSH
• fosfohydroláza PTEN MeSH
• lidé MeSH
• mutace MeSH
• nádorové buňky kultivované MeSH
• nádorové supresorové proteiny * MeSH
• proteinfosfatasy * metabolismus   MeSH
• tumor supresorové geny * MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH

The division cycle of CNS cells was arrested in G0/G1 (86.6%) and G2 (12.8%) phases in diapausing larvae of Chymomyza costata. A two-step response was observed when the diapause was induced by transferring the 3rd instar larvae from long-day to short-day conditions: first, the proportion of G2-arrested cells increased rapidly within a single day after transfer; and second, the increase of G0/G1-arrested cells started with a delay of 5 days after transfer. The changes of relative mRNA levels of seven different genes, which code for important cell cycle regulatory factors [Cyclins D and E, kinases Wee1 and Myt1, phosphatase Cdc25 (String), Dacapo (p27), and PCNA] were followed using qRT-PCR technique. Two reference genes (Rp49 and ss-tubulin) served as a background. Significant transcriptional responses to photoperiodic transfer were observed for two genes: while the relative levels of dacapo mRNA increased during the rapid entry into the G2 arrest, the pcna expression was significantly downregulated during the delayed onset of G0/G1 arrest. In addition, moderate transcriptional upregulations of the genes coding for two inhibitory kinases, wee1 and myt1 accompanied the entry into diapause. The other genes were expressed equally in all photoperiodic conditions.

• MeSH
• buněčný cyklus fyziologie   MeSH
• centrální nervový systém cytologie   MeSH
• Drosophilidae cytologie   fyziologie   MeSH
• fotoperioda MeSH
• genetická transkripce fyziologie   MeSH
• hmyzí proteiny genetika   metabolismus   MeSH
• klonování DNA MeSH
• larva cytologie   fyziologie   MeSH
• stadia vývoje MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Temperature is one of the key factors affecting growth and division of algal cells. High temperature inhibits the cell cycle in Chlamydomonas reinhardtii. At 39 °C, nuclear and cellular divisions in synchronized cultures were blocked completely, while DNA replication was partly affected. In contrast, growth (cell volume, dry matter, total protein, and RNA) remained unaffected, and starch accumulated at very high levels. The cell cycle arrest could be removed by transfer to 30 °C, but a full recovery occurred only in cultures cultivated up to 14 h at 39 °C. Thereafter, individual cell cycle processes began to be affected in sequence; daughter cell release, cell division, and DNA replication. Cell cycle arrest was accompanied by high mitotic cyclindependent kinase activity that decreased after completion of nuclear and cellular division following transfer to 30 °C. Cell cycle arrest was, therefore, not caused by a lack of cyclin-dependent kinase activity but rather a blockage in downstream processes.

• MeSH
• bílkoviny řas metabolismus   MeSH
• buněčné kultury metody   MeSH
• Chlamydomonas reinhardtii cytologie   fyziologie   MeSH
• cyklin-dependentní kinasy metabolismus   MeSH
• down regulace MeSH
• fyziologický stres MeSH
• kontrolní body buněčného cyklu * MeSH
• regulace genové exprese u rostlin MeSH
• vysoká teplota MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH