• Klíčová slova
• enzalutamid,
• MeSH
• abirateron farmakologie   terapeutické užití   MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• benzamidy farmakologie   terapeutické užití   MeSH
• doba přežití bez progrese choroby MeSH
• fenylthiohydantoin farmakologie   terapeutické užití   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   MeSH
• nitrily farmakologie   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• souhrny MeSH

Androgen and glucocorticoid receptors have been recently described as key players in processes related to prostate cancer and mainly androgen receptor's inactivation was shown as an effective way for the prostate cancer treatment. Unfortunately, androgen deprivation therapy usually loses its effectivity and the disease frequently progresses into castration-resistant prostate cancer with poor prognosis. The role of the glucocorticoid receptor is associated with the mechanism of resistance; therefore, pharmacological targeting of glucocorticoid receptor in combination with antiandrogen treatment was shown as an alternative approach in the prostate cancer treatment. We introduce here the synthesis of novel 17α- and/or 21-ester or carbamate derivatives of hydrocortisone and evaluation of their biological activity towards androgen and glucocorticoid receptors in different prostate cancer cell lines. A 17α-butyryloxy-21-(alkyl)carbamoyloxy derivative 14 was found to diminish the transcriptional activity of both receptors (in single-digit micromolar range), with comparable potency to enzalutamide towards the androgen receptor, but weaker potency compared to mifepristone towards the glucocorticoid receptor. Lead compound inhibited proliferation and the formation of cell colonies in both androgen and glucocortiocid receptors-positive prostate cancer cell lines in low micromolar concentrations. Candidate compound 14 showed to interact with both receptors in cells and inhibited the translocation of receptors to nucleus and their activation phoshorylation. Moreover, binding to receptor's ligand binding domains was assessed by molecular modelling. Lead compound also induced the accumulation of cells in G1 phase and its combination with enzalutamide was shown to be more effective than enzalutamide alone.

• MeSH
• androgenní receptory * genetika   chemie   MeSH
• androgeny farmakologie   MeSH
• antagonisté androgenů farmakologie   MeSH
• chemorezistence MeSH
• hydrokortison farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   metabolismus   MeSH
• nitrily farmakologie   MeSH
• receptory glukokortikoidů MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• Enzalutamid, studie ARCHES,
• MeSH
• analýza přežití MeSH
• antagonisté androgenů farmakologie   terapeutické užití   MeSH
• benzamidy farmakologie   terapeutické užití   MeSH
• fenylthiohydantoin farmakologie   terapeutické užití   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   MeSH
• nitrily farmakologie   terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH

Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile Gü1303 and a 3-cyano-3-aza-β-amino acid Gü2602. Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of Gü2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.

• MeSH
• hydraziny chemie   farmakologie   MeSH
• inhibitory proteas chemie   farmakologie   MeSH
• kathepsin K antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nádorové buňky kultivované MeSH
• nitrily chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• ruxolitinib,
• MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• Janus kinasy farmakologie   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nitrily farmakologie   terapeutické užití   MeSH
• primární myelofibróza * diagnóza   farmakoterapie   MeSH
• protokoly protinádorové léčby MeSH
• pyrazoly farmakologie   terapeutické užití   MeSH
• pyrimidiny farmakologie   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Schválené možnosti antiepileptické terapie v dětském věku jsou omezenější než v dospělosti a proces zařazení nového antiepileptika v dětství je většinou zdlouhavější. Cílem přehledného článku je podání ucelených informací o perampanelu, jeho nových indikacích i praktických zkušenostech. Fycompa® (perampanel - PER) má unikátní mechanismus účinku, nízký interaktivní potenciál, je bezpečný a dobře snášený a vykazuje dobrou snášenlivost i v dlouhodobém měřítku. Při správném použití může být vhodným lékem v přídatné terapii i v časných fázích léčby.

Approved options of antiepileptic treatment in children are limited in comparison with adults and the process of introduction of new antiepileptic drug is often longer. The aim of this review is to present comprehensive information concerning perampanel, its new indications and practical experience. Fycompa® (perampanel - PER) is antiepileptic drug with a specific mechanism of action low interactive potential, safe and well tolerated, with satisfactory long term tolerability profile. When rightly use it can be usable add-on therapy in early phase of treatment.

• Klíčová slova
• perampanel, Fycompa,
• MeSH
• antikonvulziva MeSH
• dítě * MeSH
• epilepsie * farmakoterapie   MeSH
• hodnocení léčiv MeSH
• lidé MeSH
• nitrily * aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• předškolní dítě MeSH
• titrace MeSH
• Check Tag
• dítě * MeSH
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• práce podpořená grantem MeSH

Importance: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS). Objective: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS. Design, Setting, and Participants: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity. Interventions: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days. Main Outcomes and Measures: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status. Results: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]). Conclusions and Relevance: In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators. Trial Registration: ClinicalTrials.gov Identifier: NCT02425644.

• MeSH
• dospělí MeSH
• hydroxybutyráty farmakologie   MeSH
• imunologické faktory terapeutické užití   MeSH
• krotonáty farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• magnetická rezonanční tomografie metody   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nitrily farmakologie   MeSH
• progrese nemoci MeSH
• relabující-remitující roztroušená skleróza farmakoterapie   MeSH
• thiazoly farmakologie   MeSH
• toluidiny farmakologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

NF-κB is activated in a variety of human cancers. However, its role in osteosarcoma (OS) remains unknown. Here, we have elucidated the implication of NF-κB in the oncogenic phenotype of OS tumor cells. We reported that activation of NF-κB was a common event in the human OS. Inhibition of NF-κB using inhibitor Bay 11-7085 repressed proliferation, survival, migration, and invasion but increased apoptosis in 143B and MG63 OS cells, indicating that NF-κB is critically implicated in the oncogenesis of OS. Notably, Bay 11-7085 not only inactivated NF-κB but also reduced the phosphorylation of AKT via its induction of PTEN, suggesting the existence of a novel NF-κB/PTEN/PI3K/AKT axis. In vivo, Bay 11-7085 suppressed tumor growth in the bone by targeting NF-κB and AKT. Interestingly, combined treatment with Bay 11-7085 and the PI3K inhibitor, LY294002, triggered an augmented antitumor effect. Our results demonstrate that NF-κB potentiates the growth and aggressiveness of OS. Pharmacological inhibition of NF-κB represents a promising therapy for the treatment of OS.

• Klíčová slova
• Bay 11-7085 Sigma-Aldrich,
• MeSH
• cílená molekulární terapie MeSH
• dimethylsulfoxid terapeutické užití   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední NOD MeSH
• nádorové buňky kultivované účinky léků   MeSH
• NF-kappa B účinky léků   MeSH
• nitrily farmakologie   terapeutické užití   MeSH
• osteosarkom * farmakoterapie   genetika   patologie   MeSH
• polymerázová řetězová reakce metody   MeSH
• protoonkogenní proteiny c-akt antagonisté a inhibitory   genetika   metabolismus   MeSH
• RNA nádorová izolace a purifikace   účinky léků   MeSH
• sulfony farmakologie   terapeutické užití   MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH

Prostate cancer (PC) is a potentially high-risk disease and the most common cancer in American men. It is a leading cause of cancer-related deaths in men in the US, second only to lung and bronchus cancer. Advanced and metastatic PC is initially treated with androgen deprivation therapy (ADT), but nearly all cases eventually progress to castrate-resistant prostate cancer (CRPC). CRPC is incurable in the metastatic stage but can be slowed by some conventional chemotherapeutics and second-generation ADT, such as enzalutamide and abiraterone. Therefore, novel therapeutic strategies are urgently needed. Prostate-specific membrane antigen (PSMA) is overexpressed in almost all aggressive PCs. PSMA is widely used as a target for PC imaging and drug delivery. Anti-PSMA monoclonal antibodies (mAbs) have been developed as bioligands for diagnostic imaging and targeted PC therapy. However, these mAbs are successfully used in PC imaging and only a few have gone beyond phase-I for targeted therapy. The 5D3 mAb is a novel, high-affinity, and fast-internalizing anti-PSMA antibody. Importantly, 5D3 mAb demonstrates a unique pattern of cellular localization to the centrosome after internalization in PSMA(+) PC3-PIP cells. These characteristics make 5D3 mAb an ideal bioligand to deliver tubulin inhibitors, such as mertansine, to the cell centrosome, leading to mitotic arrest and elimination of dividing PC cells. We have successfully developed a 5D3 mAb- and mertansine (DM1)-based antibody-drug conjugate (ADC) and evaluated it in vitro for binding affinity, internalization, and cytotoxicity. The in vivo therapeutic efficacy of 5D3-DM1 ADC was evaluated in PSMA(+) PC3-PIP and PSMA(-) PC3-Flu mouse models of human PC. This therapeutic study has revealed that this new anti-PSMA ADC can successfully control the growth of PSMA(+) tumors without inducing systemic toxicity.

• MeSH
• androsteny farmakologie   MeSH
• antagonisté androgenů farmakologie   MeSH
• antigeny povrchové metabolismus   MeSH
• benzamidy farmakologie   MeSH
• buňky PC-3 MeSH
• centrozom metabolismus   MeSH
• fenylthiohydantoin farmakologie   MeSH
• glutamátkarboxypeptidasa II metabolismus   MeSH
• imunokonjugáty farmakologie   MeSH
• lidé MeSH
• modulátory tubulinu farmakologie   MeSH
• monoklonální protilátky farmakologie   MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   metabolismus   MeSH
• nitrily farmakologie   MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related deaths of men in Western countries. Androgen deprivation therapy is initially successful, however eventually fails, and tumors progress to the more aggressive castration-resistant PCa (CRPC). Yet, androgen receptor (AR) usually remains as a major regulator of tumor cell proliferation in CRPC. Interleukin-23 (IL-23) was recently shown to promote the development of CRPC by driving AR transcription. Here we used the androgen-sensitive LNCaP, castration-resistant C4-2, and 22Rv1 cells. Interestingly, cellular senescence is induced in these human cell lines by treatment with the AR antagonists enzalutamide (ENZ) or darolutamide (ODM), which might be one underlying mechanism for inhibition of PCa cell proliferation. Treatment with IL-23 alone did not change cellular senescence levels in these cell lines, whereas IL-23 inhibited significantly cellular senescence levels induced by ENZ or ODM in both CRPC cell lines C4-2 and 22Rv1 but not in LNCaP cells. This indicates a response of IL-23 specific in CRPC cells. Generating LNCaP and C4-2 three-dimensional (3D) spheroids and treatment with AR antagonists resulted in the reduced spheroid volume and thus growth inhibition. However, the combination of AR antagonists with IL-23 did not affect the antagonist-mediated reduction of spheroid volumes. This observation was confirmed with proliferation assays using adherent monolayer cell cultures. Taken together, the data indicate that IL-23 treatment reduces the AR antagonists-induced level of cellular senescence of CRPC cells, which could be one possible mechanism for promoting castration resistance.

• MeSH
• antagonisté androgenních receptorů farmakologie   terapeutické užití   MeSH
• benzamidy farmakologie   terapeutické užití   MeSH
• fenylthiohydantoin farmakologie   terapeutické užití   MeSH
• interleukin-23 metabolismus   MeSH
• lidé MeSH
• nitrily farmakologie   terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie farmakologie   terapeutické užití   MeSH
• pyrazoly farmakologie   terapeutické užití   MeSH
• stárnutí buněk MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH