The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.
- MeSH
- apoptóza účinky léků MeSH
- bicyklické sloučeniny heterocyklické * farmakologie terapeutické užití MeSH
- difúzní velkobuněčný B-lymfom * farmakoterapie patologie MeSH
- fosfohydroláza PTEN metabolismus MeSH
- lidé MeSH
- myši SCID MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protokoly antitumorózní kombinované chemoterapie * farmakologie terapeutické užití MeSH
- protoonkogenní proteiny c-akt * metabolismus MeSH
- protoonkogenní proteiny c-bcl-2 * antagonisté a inhibitory metabolismus MeSH
- pyrimidiny * farmakologie terapeutické užití MeSH
- pyrroly farmakologie terapeutické užití MeSH
- rituximab farmakologie terapeutické užití MeSH
- sulfonamidy * farmakologie terapeutické užití MeSH
- xenogenní modely - testy antitumorózní aktivity * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
In this review, we summarize pyrroloquinoline and pyrroloisoquinoline derivatives (PQs and PIQs) that act on a broad spectrum of biological targets and are used as bacteriostatic, antiviral, plasmodial, anticancer, antidiabetic and anticoagulant agents. Many of these compounds play important roles in the study of DNA and its interactions, the regulation of the cell cycle and programmed cell death. This review involves twenty-five types of skeletally analogical compounds bearing pyrrole and (iso)quinoline scaffolds with different mutual annelations.
Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2-6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2-6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson's correlation coefficient of 0.92.
Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and in vitro and in vivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.
- MeSH
- antitumorózní látky chemická syntéza farmakologie MeSH
- apoptóza účinky léků genetika MeSH
- cisplatina farmakologie MeSH
- doxorubicin farmakologie MeSH
- fluorouracil farmakologie MeSH
- HCT116 buňky MeSH
- kolorektální nádory farmakoterapie genetika metabolismus patologie MeSH
- kontrolní body buněčného cyklu účinky léků genetika MeSH
- lidé MeSH
- myši nahé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 agonisté genetika metabolismus MeSH
- objevování léků MeSH
- proliferace buněk účinky léků MeSH
- protokoly antitumorózní kombinované chemoterapie farmakologie MeSH
- pyrroly chemická syntéza farmakologie MeSH
- regulace genové exprese u nádorů MeSH
- synergismus léků MeSH
- thiazoly chemická syntéza farmakologie MeSH
- vazba proteinů MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Influenza A virus (IAV) encodes a polymerase composed of three subunits: PA, with endonuclease activity, PB1 with polymerase activity and PB2 with host RNA five-prime cap binding site. Their cooperation and stepwise activation include a process called cap-snatching, which is a crucial step in the IAV life cycle. Reproduction of IAV can be blocked by disrupting the interaction between the PB2 domain and the five-prime cap. An inhibitor of this interaction called pimodivir (VX-787) recently entered the third phase of clinical trial; however, several mutations in PB2 that cause resistance to pimodivir were observed. First major mutation, F404Y, causing resistance was identified during preclinical testing, next the mutation M431I was identified in patients during the second phase of clinical trials. The mutation H357N was identified during testing of IAV strains at Centers for Disease Control and Prevention. We set out to provide a structural and thermodynamic analysis of the interactions between cap-binding domain of PB2 wild-type and PB2 variants bearing these mutations and pimodivir. Here we present four crystal structures of PB2-WT, PB2-F404Y, PB2-M431I and PB2-H357N in complex with pimodivir. We have thermodynamically analysed all PB2 variants and proposed the effect of these mutations on thermodynamic parameters of these interactions and pimodivir resistance development. These data will contribute to understanding the effect of these missense mutations to the resistance development and help to design next generation inhibitors.
- MeSH
- krystalografie rentgenová MeSH
- kvantová teorie MeSH
- molekulární modely MeSH
- mutace genetika MeSH
- mutantní proteiny metabolismus MeSH
- podjednotky proteinů antagonisté a inhibitory chemie metabolismus MeSH
- proteinové domény MeSH
- pyridiny chemie farmakologie MeSH
- pyrimidiny chemie farmakologie MeSH
- pyrroly chemie farmakologie MeSH
- RNA-dependentní RNA-polymerasa antagonisté a inhibitory chemie metabolismus MeSH
- termodynamika MeSH
- virová léková rezistence účinky léků MeSH
- virové proteiny antagonisté a inhibitory chemie metabolismus MeSH
- virus chřipky A účinky léků enzymologie MeSH
- Publikační typ
- časopisecké články MeSH
Conducting polymers (CP) can be used as pH- and/or electro-responsive components in various bioapplications, for example, in 4D smart scaffolds. The ability of CP to maintain conductivity under physiological conditions is, therefore, their crucial property. Unfortunately, the conductivity of the CP rapidly decreases in physiological environment, as their conducting salts convert to non-conducting bases. One of the promising solutions how to cope with this shortcoming is the use of alternative "doping" process that is not based on the protonation of CP with acids but on interactions relying in acidic hydrogen bonding. Therefore, the phosphonates (dimethyl phosphonate, diethyl phosphonate, dibutyl phosphonate, or diphenyl phosphonate) were used to re-dope two most common representatives of CP, polyaniline (PANI) and polypyrrole (PPy) bases. As a result, PANI doped with organic phosphonates proved to have significantly better stability of conductivity under different pH. It has also been shown that cytotoxicity of studied materials determined on embryonic stem cells and their embryotoxicity, determined as the impact on cardiomyogenesis and erythropoiesis, depend both on the polymer and phosphonate types used. With the exception of PANI doped with dibutyl phosphonate, all PPy-based phosphonates showed better biocompatibility than the phosphonates based on PANI.
- MeSH
- aniliny chemie farmakologie MeSH
- biokompatibilní materiály chemie farmakologie MeSH
- buněčná diferenciace účinky léků MeSH
- buněčné linie MeSH
- elektrická vodivost MeSH
- koncentrace vodíkových iontů MeSH
- myší embryonální kmenové buňky MeSH
- myši MeSH
- organofosfonáty chemie MeSH
- polymery chemie farmakologie MeSH
- pyrroly chemie farmakologie MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
In the field of tissue engineering, much research has been devoted to the surface topography of conductive materials. However, less work has been carried out on how the electrical stimulation of such materials influences nerve regeneration. Here, we investigated the effect of electrical stimulation on randomly- and uniaxially-aligned polypyrrole-coated cellulose acetate butyrate (PPy/CAB) nanofibers. First, SEM revealed that the conducting PPy coverage resulted in dramatic changes to the nanofiber morphology. In turn, these changes led to an increase in the sample wettability. Fourier transform spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) confirmed the presence of a PPy layer. Second, human neuroblastoma cells (SH-SY5Y) were seeded on the PPy/CAB nanofibers and stimulated by 100 mV mm-1 at 1 Hz pulses in vitro. We demonstrated that either with or without this electrical stimulation both nanofiber alignment and PPy coverage had a strong influence on cell morphology and attachment. Moreover, fluorescence microscopy revealed that the cells stimulated on PPy/CAB had longer neurite outgrowth. Collectively, our results shed light on the combined effect of scaffold morphology and external stimulation on neuronal cell behavior.
- MeSH
- buněčná adheze účinky léků MeSH
- celulosa analogy a deriváty farmakologie toxicita MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nanovlákna chemie toxicita MeSH
- neurity účinky léků MeSH
- neuronální růst účinky léků MeSH
- polymery farmakologie toxicita MeSH
- proliferace buněk účinky léků MeSH
- pyrroly farmakologie toxicita MeSH
- smáčivost MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
S-nitrosoglutathione reductase (GSNOR) exerts crucial roles in the homeostasis of nitric oxide (NO) and reactive nitrogen species (RNS) in plant cells through indirect control of S-nitrosation, an important protein post-translational modification in signaling pathways of NO. Using cultivated and wild tomato species, we studied GSNOR function in interactions of key enzymes of reactive oxygen species (ROS) metabolism with RNS mediated by protein S-nitrosation during tomato root growth and responses to salinity and cadmium. Application of a GSNOR inhibitor N6022 increased both NO and S-nitrosothiol levels and stimulated root growth in both genotypes. Moreover, N6022 treatment, as well as S-nitrosoglutathione (GSNO) application, caused intensive S-nitrosation of important enzymes of ROS metabolism, NADPH oxidase (NADPHox) and ascorbate peroxidase (APX). Under abiotic stress, activities of APX and NADPHox were modulated by S-nitrosation. Increased production of H2O2 and subsequent oxidative stress were observed in wild Solanumhabrochaites, together with increased GSNOR activity and reduced S-nitrosothiols. An opposite effect occurred in cultivated S. lycopersicum, where reduced GSNOR activity and intensive S-nitrosation resulted in reduced ROS levels by abiotic stress. These data suggest stress-triggered disruption of ROS homeostasis, mediated by modulation of RNS and S-nitrosation of NADPHox and APX, underlies tomato root growth inhibition by salinity and cadmium stress.
- MeSH
- aldehydoxidoreduktasy metabolismus MeSH
- askorbátperoxidasa metabolismus MeSH
- benzamidy chemie metabolismus farmakologie MeSH
- chlorid sodný farmakologie MeSH
- fyziologický stres MeSH
- kadmium toxicita MeSH
- kořeny rostlin účinky léků růst a vývoj metabolismus MeSH
- NADPH-oxidasy metabolismus MeSH
- nitrosace MeSH
- oxid dusnatý metabolismus MeSH
- oxidační stres účinky léků MeSH
- peroxid vodíku metabolismus MeSH
- pyrroly chemie metabolismus farmakologie MeSH
- reaktivní formy dusíku chemie metabolismus MeSH
- reaktivní formy kyslíku chemie metabolismus MeSH
- regulace genové exprese u rostlin účinky léků MeSH
- rostlinné proteiny metabolismus MeSH
- S-nitrosoglutathion farmakologie MeSH
- S-nitrosothioly metabolismus MeSH
- Solanum lycopersicum účinky léků růst a vývoj metabolismus MeSH
- Solanum růst a vývoj metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Léčba psoriatické artritidy (PsA) vyžaduje multidisciplinární přístup celé řady specializací k dosažení remise, či alespoň nízké aktivity všech projevů onemocnění, jak muskuloskeletárních, tak kožních. Postupem let přibývají další terapeutické prostředky umožňující efektivnější léčbu nemocných s obzvlášť rezistentní formou PsA na konvenční terapii. Tofacitinib je selektivní inhibitor Janusových kináz, který prokázal svůj efekt a bezpečnost v celé řadě klinických studií programu OPAL u PsA. Data získaná z klinických studií vedly k zavedení tofacitinibu pro léčbu středně až vysoce aktivní PsA u které došlo k selhání předchozí konvenční, či biologické terapie. Tento přehled se zabývá tofacitinibem v indikaci u PsA.
The treatment of psoriatic arthritis (PsA) requires a multidisciplinary approach of a wide range of specializations in order to achieve remission, or at least a low activity of all disease manifestations, both musculoskeletal and dermal ones. Over the years, more therapeutic options have been developed allowing a more effective treatment in patients with a form of PsA particularly resistant to conventional therapy. Tofacitinib is a selective Janus kinase inhibitor whose efficacy and safety has been shown in a number of clinical trials of the OPAL programme in PsA. Data obtained from clinical trials have led to the introduction of tofacitinib in the treatment of moderately to highly active PsA in which there was failure of the previous conventional or biological therapy. This review deals with tofacitinib indicated to treat PsA.
- Klíčová slova
- tofacitinib, studie OPAL-BEYOND, studie OPAL-BROADEN,
- MeSH
- Janus kinasa 3 antagonisté a inhibitory terapeutické užití MeSH
- klinické zkoušky, fáze III jako téma MeSH
- lidé MeSH
- piperidiny farmakologie terapeutické užití MeSH
- psoriatická artritida * farmakoterapie MeSH
- pyrimidiny farmakologie terapeutické užití MeSH
- pyrroly farmakologie terapeutické užití MeSH
- randomizované kontrolované studie jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Klíčová slova
- Studie OCTAVE Sustain - tofacitinib (XELJANZ),
- MeSH
- hodnocení rizik MeSH
- indukční chemoterapie normy MeSH
- inhibitory Janus kinas farmakologie terapeutické užití MeSH
- lidé MeSH
- nežádoucí účinky léčiv epidemiologie etiologie MeSH
- piperidiny farmakologie škodlivé účinky terapeutické užití MeSH
- pyrimidiny farmakologie škodlivé účinky terapeutické užití MeSH
- pyrroly farmakologie škodlivé účinky terapeutické užití MeSH
- udržovací chemoterapie MeSH
- ulcerózní kolitida * farmakoterapie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
