- Publikační typ
- abstrakt z konference MeSH
BACKGROUND AND PURPOSE: Cyclin-dependent kinase 5 (CDK5) has recently emerged as an attractive target in several tumour entities. Inhibition of CDK5 has been shown to have anti-angiogenic effects in vitro and in vivo. However, potent inhibitors of CDK5, which can be applied in vivo, are still scarce. We have recently developed a new series of 5-substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines that show a preference for inhibiting CDK5 and tested them in vitro and in vivo in a murine model of hepatocellular carcinoma. EXPERIMENTAL APPROACH: All compounds were initially examined for effects on proliferation of HUVECs. The most potent compounds were then tested on migration, and one of them, LGR2674, was selected for assessing effects on nuclear fragmentation, cell cycle, cell viability and metabolic activity. Furthermore, LGR2674 was tested in a tube formation assay and in vivo in a murine model of hepatocellular carcinoma, induced by s.c. injection of HUH7 cells (measurement of in vivo toxicity, tumour vascularization, tumour cell proliferation and tumour size). KEY RESULTS: LGR2674 showed an EC50 in the low nanomolar range in the proliferation and migration assays. Cytotoxic effects started at 50 nM, a concentration that did not influence the cell cycle. In vivo, LGR2674 was well tolerated and caused a clear reduction in vessel density in the tumours; also tumour cell proliferation was inhibited and tumour growth retarded. CONCLUSIONS AND IMPLICATIONS: Pyrazolo[4,3-d]pyrimidine is a novel scaffold for the development of potent CDK inhibitors with in vivo potential. Such structures are good candidates for broadening our pharmacological arsenal against various tumours.
- MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- cyklin-dependentní kinasa 5 antagonisté a inhibitory MeSH
- experimentální nádory jater farmakoterapie patologie MeSH
- inhibitory angiogeneze chemická syntéza chemie farmakologie MeSH
- kultivované buňky MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- myši MeSH
- pohyb buněk účinky léků MeSH
- proliferace buněk účinky léků MeSH
- pyrazoly chemická syntéza chemie farmakologie MeSH
- pyrimidiny chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We have prepared and studied a series of new brassinosteroid derivatives with a p-substituted phenyl group in the side chain. To obtain the best comparison between molecular docking and biological activities both types of brassinosteroids were synthesized; 6-ketones, 10 examples, and B-lactones, 8 examples. The phenyl group was introduced into the steroid skeleton by Horner-Wadsworth-Emmons. The docking studies were carried out using AutoDock Vina 1.05. Plant biological activities were established using different brassinosteroid bioassays in comparison with natural brassinosteroids. Differences in the production of the plant hormone ethylene were also observed in etiolated pea seedlings after treatment with new brassinosteroids. The most active compounds were lactone 8f and 6-oxo derivatives 8c and 9c, their biological activities were comparable or even better than naturally occurring brassinolide. Finally the cytotoxicity of the new derivatives was studied using human normal and cancer cell lines.
- MeSH
- antitumorózní látky chemie metabolismus farmakologie MeSH
- Arabidopsis metabolismus MeSH
- brassinosteroidy chemie metabolismus farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie MeSH
- proteinkinasy metabolismus MeSH
- proteiny huseníčku metabolismus MeSH
- regulátory růstu rostlin metabolismus MeSH
- simulace molekulového dockingu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
Signaling through the androgen receptor (AR) plays a critical role in prostate cancer progression. The AR is a classical nuclear receptor (NR) providing a link between signaling molecule and transcription response. Histone deacetylase inhibitors- (HDACI) have antiproliferative and proapoptotic effects on prostate cancer cells and their implication in silence AR signaling may have potential therapeutic use. We aimed to study the inhibitory effects of the corepressor SMRT (Silencing Mediator for Retinoid and Thyroid -hormone receptors) which forms a complex together with nuclear receptor corepressor (N-CoR) and with histone deacetylase 3 (HDAC3) on AR activity.The androgen-sensitive prostate cancer cell line LNCaP and androgen-insensitive prostate cancer cell line C4-2 both AR-positive, and androgen-insensitive DU145 and PC3 prostate cancer cell lines were treated with two HDACIs, sodium butyrate (NaB) and/or trichostatin A (TSA). We amplified immunoprecipitated DNA by conventional PCR and in the -following step we used the chromatin immunoprecipitation (ChIP) analysis coupled with quantitative PCR for monitoring NaB induced formation of AR-SMRT/N-CoR complex binding on the PSA promoter. The co-immunoprecipitation assay revealed increase in AR-SMRT formation in NaB treated cells. Simultaneously, the Western blot analysis showed a significant decrease in AR protein expression. In conclusion, the inhibitory effect of NaB on AR gene expression seems to be specific and unique for prostate cancer AR-positive cell lines and corresponds with its ability to stimulate AR-SMRT complex formation. We suggest that AR and SMRT/N-CoR corepressors may form a stable complex in vitro and NaB may facilitate the interaction between AR nuclear steroid receptor and SMRT corepressor prote.
- MeSH
- androgenní receptory metabolismus MeSH
- butyráty farmakologie MeSH
- histondeacetylasa 2 analýza MeSH
- histondeacetylasy analýza metabolismus MeSH
- inhibitory histondeacetylas terapeutické užití MeSH
- korepresor 1 jaderného receptoru metabolismus MeSH
- kyseliny hydroxamové farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory prostaty farmakoterapie metabolismus MeSH
- promotorové oblasti (genetika) MeSH
- prostatický specifický antigen genetika MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antitumorózní látky farmakologie chemie MeSH
- inhibitory enzymů farmakologie chemie MeSH
- inhibitory růstu farmakologie chemie MeSH
- jaderné proteiny MeSH
- kinasy CDC2-CDC28 antagonisté a inhibitory chemie MeSH
- nádorové buněčné linie MeSH
- protoonkogenní proteiny metabolismus MeSH
- puriny farmakologie chemie MeSH
- vazebná místa MeSH
- MeSH
- antitumorózní látky farmakologie chemická syntéza chemie MeSH
- cyklin-dependentní kinasy antagonisté a inhibitory MeSH
- finanční podpora výzkumu jako téma MeSH
- kinasy CDC2-CDC28 antagonisté a inhibitory MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové supresorové proteiny metabolismus MeSH
- proliferace buněk účinky léků MeSH
- proteiny buněčného cyklu metabolismus MeSH
- puriny farmakologie chemická syntéza chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
Autoři popisují případ 41leté pacientky s diagnózou erythema nodosum jako projevem ulcerózní kolitidy. Zdůrazňují důležitost komplexního pohledu na toto kožní onemocnění, na jehož vzniku se může podílet řada faktorů. Dle údajů odborné literatury bývá nespecifický střevní zánět příčinou vzniku erythema nodosum asi v 1–2 %.
The authors describe a case of 41-year-old patient with erythema nodosum as a manifestation of colitis ulcerosa. They stress the importance of complex look at this skin disease, which can be caused by many factors. Non-specific intestinal inflammation can be a cause of the erythema nodosum in 1–2 %.
