BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors (FAKi), alone or in combination with SOR, using in vitro and in vivo models of HCC. METHODS: The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods. RESULTS: TAE226 was the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of FAK nuclear interactome. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation caused a decrease in the nuclear amount of HDAC1/2 and a consequent increase of the histone H3 lysine 27 acetylation, thus counteracting histone H3 lysine 27 trimethylation. CONCLUSIONS: Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy.

• MeSH
• epigeneze genetická genetika   MeSH
• hepatocelulární karcinom farmakoterapie   MeSH
• lidé MeSH
• morfoliny farmakologie   terapeutické užití   MeSH
• myši inbrední NOD MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory jater farmakoterapie   MeSH
• proliferace buněk MeSH
• protokoly antitumorózní kombinované chemoterapie farmakologie   terapeutické užití   MeSH
• sorafenib farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Hydrogen sulphide (H2S) is involved in the physiology and pathophysiology of different cell types, but little is known about its role in sperm cells. Because of its reducing properties, we hypothesise that H2S protects spermatozoa against the deleterious effects of oxidative stress, a condition that is common to several male fertility disorders. This study aimed i) to determine the total antioxidant capacities of Na2S and GYY4137, which are fast- and slow-releasing H2S donors, respectively, and ii) to test whether H2S donors are able to protect spermatozoa against oxidative stress. We found that Na2S and GYY4137 show different antioxidant properties, with the total antioxidant capacity of Na2S being mostly unstable and even undetectable at 150 µM. Moreover, both H2S donors preserve sperm motility and reduce acrosome loss, although the effects were both dose and donor dependent. Within the range of concentrations tested (3-300 µM), GYY4137 showed positive effects on sperm motility, whereas Na2S was beneficial at the lowest concentration but detrimental at the highest. Our findings show that Na2S and GYY4137 have different antioxidant properties and suggest that both H2S donors might be used as in vitro therapeutic agents against oxidative stress in sperm cells, although the optimal therapeutic range differs between the compounds.

• MeSH
• antioxidancia farmakologie   MeSH
• lidé MeSH
• morfoliny farmakologie   MeSH
• motilita spermií účinky léků   MeSH
• organothiofosforové sloučeniny farmakologie   MeSH
• oxidační stres účinky léků   MeSH
• prasata MeSH
• spermie účinky léků   MeSH
• sulfan metabolismus   MeSH
• sulfidy farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

We report the design, synthesis and biological evaluation of 17 novel 8-aryl-2-morpholino-3,4-dihydroquinazoline derivatives based on the standard model of DNA-PK and PI3K inhibitors. Novel compounds are sub-divided into two series where the second series of five derivatives was designed to have a better solubility profile over the first one. A combination of in vitro and in silico techniques suggested a plausible synergistic effect with doxorubicin of the most potent compound 14d on cell proliferation via DNA-PK and poly(ADP-ribose) polymerase-1 (PARP-1) inhibition, while alone having a negligible effect on cell proliferation.

• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buňky HT-29 MeSH
• chinazolinony chemická syntéza   farmakologie   toxicita   MeSH
• doxorubicin farmakologie   MeSH
• inhibitory enzymů chemická syntéza   farmakologie   toxicita   MeSH
• jaderné proteiny antagonisté a inhibitory   MeSH
• lidé MeSH
• morfoliny chemická syntéza   farmakologie   toxicita   MeSH
• myši MeSH
• outbrední kmeny zvířat MeSH
• poly-ADP-ribóza-polymeráza 1 antagonisté a inhibitory   MeSH
• proliferace buněk účinky léků   MeSH
• proteinkinasa aktivovaná DNA antagonisté a inhibitory   MeSH
• racionální návrh léčiv MeSH
• synergismus léků MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We explored possibility that sodium/calcium exchanger 1 (NCX1) is involved in pH modulation and apoptosis induction in GYY4137 treated cells. We have shown that although 10 days treatment with GYY4137 did not significantly decreased volume of tumors induced by colorectal cancer DLD1 cells in nude mice, it already induced apoptosis in these tumors. Treatment of DLD1 and ovarian cancer A2780 cells with GYY4137 resulted in intracellular acidification in a concentration-dependent manner. We observed increased mRNA and protein expression of both, NCX1 and sodium/hydrogen exchanger 1 (NHE1) in DLD1-induced tumors from GYY4137-treated mice. NCX1 was coupled with NHE1 in A2780 and DLD1 cells and this complex partially disintegrated after GYY4137 treatment. We proposed that intracellular acidification is due to uncoupling of NCX1/NHE1 complex rather than blocking of the reverse mode of NCX1, probably due to internalization of NHE1. Results might contribute to understanding molecular mechanism of H2S-induced apoptosis in tumor cells.

• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• morfoliny farmakologie   MeSH
• myši nahé MeSH
• nádorové buněčné linie MeSH
• organothiofosforové sloučeniny farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• pumpa pro výměnu sodíku a vápníku metabolismus   MeSH
• sodíko-vodíkový výměnný transportér 1 metabolismus   MeSH
• sulfan metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A new thiourea ligand (HL), namely N-(4-chlorophenyl)morpholine-4-carbothioamide and its Co(III), Ni(II) and Ag(I) complexes (1a, 1b and 1c) were synthesized and investigated by Fourier-transform infrared, 1H NMR and UV-visible spectroscopies. The compounds HL and 1c were characterized by single-crystal X-ray crystallography revealing the triclinic space group P[Formula: see text] for both compounds. The inhibitory effect of HL ligand, 1a, 1b, and 1c complexes was investigated with in vitro tests on Gram-positive and Gram-negative bacteria. For the 1c complex, the results showed that the coordination of the HL to Ag(I) ion increased its antibacterial effect especially against E. coli. The assays also indicated that for the same bacteria strains, the new complexes showed higher activity than the ligand, with the relative activity 1c > 1b > 1a > HL. Moreover, all samples were more suitable antimicrobial agents against the Gram-negative than those of the Gram-positive bacteria. Eventually, the relationship between the structure and bactericidal activities of these specimens was examined by calculating frontier molecular orbital (HOMO and LUMO) energies using density functional theory method at the 6-31 G*/LANL2DZ level of theory.

• MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• gramnegativní bakterie účinky léků   MeSH
• grampozitivní bakterie účinky léků   MeSH
• komplexní sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• krystalografie rentgenová MeSH
• magnetická rezonanční spektroskopie MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• morfoliny chemická syntéza   chemie   farmakologie   MeSH
• spektrofotometrie ultrafialová MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• thioamidy chemická syntéza   chemie   farmakologie   MeSH
• thiomočovina metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH

Buparlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor and is currently under clinical evaluation for the treatment of different cancers. Because PI3K signalling is related to cell proliferation and resistance to chemotherapy, new therapeutic approaches are focused on combining PI3K inhibitors with other anti-cancer therapeutics. Carbonyl-reducing enzymes catalyse metabolic detoxification of anthracyclines and reduce their cytotoxicity. In the present work, the effects of buparlisib were tested on six human recombinant carbonyl-reducing enzymes: AKR1A1, AKR1B1, AKR1B10, AKR1C3, and AKR7A2 from the aldo-keto reductase superfamily and CBR1 from the short-chain dehydrogenase/reductase superfamily, all of which participate in the metabolism of daunorubicin. Buparlisib exhibited the strongest inhibitory effect on recombinant AKR1C3, with a half-maximal inhibitory concentration (IC50) of 9.5 μM. Its inhibition constant Ki was found to be 14.0 μM, and the inhibition data best fitted a mixed-type mode with α = 0.6. The same extent of inhibition was observed at the cellular level in the human colorectal carcinoma HCT 116 cell line transfected with a plasmid encoding the AKR1C3 transcript (IC50 = 7.9 μM). Furthermore, we performed an analysis of flexible docking between buparlisib and AKR1C3 and found that buparlisib probably occupies a part of the binding site for a cofactor most likely via the trifluoromethyl group of buparlisib interacting with catalytic residue Tyr55. In conclusion, our results show a novel PI3K-independent effect of buparlisib that may improve therapeutic efficacy and safety of daunorubicin by preventing its metabolism by AKR1C3.

• MeSH
• aldo-keto reduktasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• aminopyridiny chemie   metabolismus   farmakologie   MeSH
• daunomycin metabolismus   MeSH
• HCT116 buňky MeSH
• inhibiční koncentrace 50 MeSH
• katalytická doména MeSH
• kinetika MeSH
• lidé MeSH
• morfoliny chemie   metabolismus   farmakologie   MeSH
• protein AKR1C3 antagonisté a inhibitory   chemie   metabolismus   MeSH
• rekombinantní proteiny biosyntéza   izolace a purifikace   metabolismus   MeSH
• simulace molekulového dockingu MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• antimykotické laky, amorolfin,
• MeSH
• antifungální látky aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• aplikace kožní MeSH
• ciklopirox aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• morfoliny aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• onychomykóza * etiologie   terapie   MeSH
• Check Tag
• lidé MeSH

• Klíčová slova
• buparlisib,
• MeSH
• aminopyridiny farmakologie   terapeutické užití   MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• doba přežití bez progrese choroby MeSH
• dvojitá slepá metoda MeSH
• fosfatidylinositol-3-kinasy třídy III farmakologie   terapeutické užití   MeSH
• fulvestrant * farmakologie   terapeutické užití   MeSH
• lidé MeSH
• morfoliny farmakologie   terapeutické užití   MeSH
• nádory prsu * farmakoterapie   MeSH
• protokoly antitumorózní kombinované chemoterapie MeSH
• randomizované kontrolované studie jako téma MeSH
• triple-negativní karcinom prsu farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• komentáře MeSH
• souhrny MeSH

PURPOSE: The aim of this prospective study was to compare in non-Asian subjects the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of two short-acting cardioselective β1-adrenergic antagonists, landiolol and esmolol, after administration of three different bolus dosages. MATERIALS AND METHODS: We conducted a single-center, prospective, double-blinded, randomized study in three cross-over periods with 12 healthy subjects (7 women and 5 men, mean age of 24.5 ± 6.9 years) each receiving three doses of landiolol (0.1, 0.2, and 0.3 mg/kg BW) either in a newly developed concentrate i.v. formulation (Rapibloc® 20 mg/2 mL concentrate) or a lyophilized formulation, or three doses of esmolol (0.5, 1, and 1.5 mg/kg BW) in an i.v. formulation (Brevibloc® 100 mg/10 mL). PK and PD parameters, safety, and tolerability were assessed. FINDINGS: Results of the two landiolol formulations were reported previously and were similar. For the landiolol concentrate formulation and esmolol, maximum blood concentrations were rapidly reached (mean t max ranged between 1.8 and 3.0 min for landiolol and 1.8 to 2.4 min for esmolol). The parent drugs disappeared very fast from the blood stream, with a t 1/2 of 3.2 ± 1.2 (SD) minutes and 3.7 ± 2.1 (SD) minutes for the low doses of landiolol and esmolol, respectively. Despite comparable injection rates (0.1 or 0.5 mg/kg/15 s for landiolol and esmolol, respectively), the onset of significant heart rate reduction occurred earlier in response to landiolol (1 min) than in response to esmolol (2 min). In addition, significantly lower heart rate values were obtained at every dose level of landiolol, in comparison to esmolol (p < 0.05). Both compounds reduced the systolic blood pressure to a comparable degree. Especially at the highest dose, the duration of blood pressure reduction was longer under esmolol compared to landiolol. Seven mild to moderate adverse events occurred after administration of landiolol, and five occurred after administration of esmolol. No serious adverse events were reported in this study. IMPLICATIONS: Heart rate reduction induced by a new liquid formulation of landiolol occurred faster, was more pronounced, and lasted longer than the effects of corresponding standard esmolol doses. Both agents reduced systolic blood pressure to a comparable degree, but the blood pressure decrease lasted longer after esmolol infusion. The local tolerance and safety profiles of the two formulations were similar. In summary, compared to esmolol, landiolol shows a more prominent and pronounced bradycardic effect in relation to its blood pressure-lowering effect, an action profile that might be of specific advantage in the perioperative setting. TRIAL REGISTRATION: NCT01652898 and 2012-002127-14. https://clinicaltrials.gov/ct2/show/NCT01652898?term=landiolol&rank=7.

• MeSH
• běloši * MeSH
• beta blokátory aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• lidé MeSH
• mladý dospělý MeSH
• močovina aplikace a dávkování   analogy a deriváty   farmakokinetika   farmakologie   MeSH
• morfoliny aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• propanolaminy aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• prospektivní studie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

This study elucidated the stage-specific roles of FGF2 signaling during neural development using in-vitro human embryonic stem cell-based developmental modeling. We found that the dysregulation of FGF2 signaling prior to the onset of neural induction resulted in the malformation of neural rosettes (a neural tube-like structure), despite cells having undergone neural induction. The aberrant neural rosette formation may be attributed to the misplacement of ZO-1, which is a polarized tight junction protein and shown co-localized with FGF2/FGFR1 in the apical region of neural rosettes, subsequently led to abnormal neurogenesis. Moreover, the FGF2 signaling inhibition at the stage of neural rosettes caused a reduction in cell proliferation, an increase in numbers of cells with cell-cycle exit, and premature neurogenesis. These effects may be mediated by NUMB, to which expression was observed enriched in the apical region of neural rosettes after FGF2 signaling inhibition coinciding with the disappearance of PAX6+/Ki67+ neural stem cells and the emergence of MAP2+ neurons. Moreover, our results suggested that the hESC-based developmental system reserved a similar neural stem cell niche in vivo.

• MeSH
• buněčná diferenciace účinky léků   MeSH
• buněčné linie MeSH
• časosběrné zobrazování MeSH
• chromony farmakologie   MeSH
• fibroblastový růstový faktor 2 farmakologie   MeSH
• imunohistochemie MeSH
• lidé MeSH
• lidské embryonální kmenové buňky cytologie   metabolismus   MeSH
• malá interferující RNA metabolismus   MeSH
• membránové proteiny metabolismus   MeSH
• morfoliny farmakologie   MeSH
• nervové kmenové buňky cytologie   metabolismus   MeSH
• neurogeneze účinky léků   MeSH
• neurony cytologie   metabolismus   MeSH
• protein zonula occludens 1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• proteiny asociované s mikrotubuly metabolismus   MeSH
• proteiny nervové tkáně metabolismus   MeSH
• pyrimidiny farmakologie   MeSH
• receptor fibroblastových růstových faktorů, typ 1 metabolismus   MeSH
• RNA interference MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH