Herein, we describe the general design, synthesis, characterization, and biological activity of new multitargeting Pt(IV) prodrugs that combine antitumor cisplatin and dasatinib, a potent inhibitor of Src kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive activities in tumor cell lines in both two-dimensional (2D) monolayers of cell cultures and three-dimensional (3D) spheroids. We show that the cisplatin moiety and dasatinib in the investigated Pt(IV) complexes are both involved in the mechanism of action in MCF7 breast cancer cells and act synergistically. Thus, combining dasatinib and cisplatin into one molecule, compared to using individual components in a mix, may bring several advantages, such as significantly higher activity in cancer cell lines and higher selectivity for tumor cells. Most importantly, Pt(IV)-dasatinib complexes hold significant promise for potential anticancer therapies by targeting epithelial-mesenchymal transition, thus preventing the spread and metastasis of tumors, a value unachievable by a simple combination of both individual components.
- MeSH
- cisplatina * farmakologie MeSH
- dasatinib * farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádorové buněčné linie MeSH
- organoplatinové sloučeniny farmakologie chemie chemická syntéza MeSH
- prekurzory léčiv * farmakologie chemie chemická syntéza MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky * farmakologie chemie chemická syntéza MeSH
- screeningové testy protinádorových léčiv MeSH
- synergismus léků * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In this work, the mechanism underlying the anticancer activity of a photoactivatable Ir(III) compound of the type [Ir(C^N)2(dppz)][PF6] where C^N = 1-methyl-2-(2'-thienyl)benzimidazole (complex 1) was investigated. Complex 1 photoactivated by visible light shows potent activity against highly aggressive and poorly treatable Rhabdomyosarcoma (RD) cells, the most frequent soft tissue sarcomas of children. This remarkable activity of 1 was observed not only in RD cells cultured in 2D monolayers but, more importantly, also in 3D spheroids, which resemble in many aspects solid tumors and serve as a promising model to mimic the in vivo situation. Importantly, photoactivated 1 kills not only differentiated RD cells but also even more effectively cancer stem cells (CSCs) of RD. One of the factors responsible for the activity of irradiated 1 in RD CSCs is its ability to produce ROS in these cells more effectively than in differentiated RD cells. Moreover, photoactivated 1 caused in RD differentiated cells and CSCs a significant decrease of mitochondrial membrane potential and promotes opening mitochondrial permeability transition pores in these cells, a mechanism that has never been demonstrated for any other metal-based anticancer complex. The results of this work give evidence that 1 has a potential for further evaluation using in vivo models as a promising chemotherapeutic agent for photodynamic therapy of hardly treatable human Rhabdomyosarcoma, particularly for its activity in both stem and differentiated cancer cells.
- MeSH
- dítě MeSH
- iridium farmakologie MeSH
- komplexní sloučeniny * farmakologie MeSH
- lidé MeSH
- mitochondrie MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky MeSH
- protinádorové látky * farmakologie MeSH
- rhabdomyosarkom * farmakoterapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The possibilities of substantial long-term improvement of predictive timing might be sometimes seen as limited, with scanty information of neural substrates underlying the potential learning process. To address this issue, we have investigated the performance of 21 baseball professionals and 21 matched controls in a predictive motor timing task previously shown to engage the cerebellum. Baseball players, hypothesized as a model of overtraining of the prediction of future state of the surroundings, showed significantly higher quantitative performance than nonathletic controls, with a substantial part of the baseball players reaching levels far beyond the range observed in common population. Furthermore, the qualitative performance profile of baseball players under various conditions as target speed and acceleration modes did not differ from the profile of healthy controls. Our results suggest that regular exigent training has the potential to vastly improve predictive motor timing. Moreover, the quantitative but not qualitative difference in the performance profile allows us to hypothesize that the selective honing of the same cerebellar processes and networks as in non-trained individuals is the substrate for the quantitative performance improvement, without substantial engagement of further neural nodes.
- MeSH
- baseball MeSH
- cvičení fyziologie MeSH
- dospělí MeSH
- lidé MeSH
- mozek fyziologie MeSH
- psychomotorický výkon fyziologie MeSH
- sportovci * MeSH
- učení fyziologie MeSH
- vnímání času fyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Onemocnění ruka-noha-ústa („Hand foot and mouth disease“) je virové exantémové onemocnění běžné v dětském věku, které se nezřídka objevuje i u dospělých. Autoři předkládají popisy případů tří pacientů z období pozorované ve stejném období v hradeckém regionu. Uvádíme popis klinického obrazu onemocnění, možnosti laboratorní diagnostiky, diferenciální diagnózy onemocnění, komplikace, možné epidemiologické souvislosti. Klíčová slova: onemocnění ruka-noha-ústa – virový exantém – enteroviry
Hand foot and mouth disease is an viral exanthematic disease typical for children, often ocurring in adults as well. Authors report three cases observed in the same period in the region of Hradec Králové. They describe clinical picture, laboratory diagnostic methods, differential diagnosis, complications and possible epidemiologic relations of the disease. Key words: hand foot and mouth disease – viral exanthems – Enteroviruses
- Klíčová slova
- virový exantém, enteroviry, viry coxsackie A16,
- MeSH
- enterovirus A lidský * MeSH
- exantém MeSH
- horečka MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- nemoc rukou, nohou a úst * diagnóza etiologie patofyziologie MeSH
- příznaky a symptomy MeSH
- Check Tag
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Autorka článku se zaměřuje na zvláštnosti přístupu k ošetřování ran u klientů s demencí, zdůrazňuje specifika spolupráce s klientem a význam prevence. Poukazuje na využití vhodného převazového materiálu a postoj zdravotnického personálu ke klientům s demencí při hospitalizaci.
- Klíčová slova
- spolupráce, prevence,
- MeSH
- dekubity terapie MeSH
- demence ošetřování psychologie MeSH
- hojení ran fyziologie účinky léků MeSH
- lidé MeSH
- obvazy hydrokoloidní využití MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Reported herein is a detailed biochemical and molecular biophysics study of the molecular mechanism of action of antitumor dinuclear Pt(II) complex [{PtCl(DACH)}(2)-mu-Y](4+) [DACH=1,2-diaminocyclohexane, Y=H(2)N(CH(2))(6)NH(2)(CH(2))(2)NH(2)(CH(2))(6)NH(2)] (complex 1). This new, long-chain bifunctional dinuclear Pt(II) complex is resistant to metabolic decomposition by sulfur-containing nucleophiles. The results show that DNA adducts of 1 can largely escape repair and yet inhibit very effectively transcription so that they should persist longer than those of conventional cisplatin. Hence, they could trigger a number of downstream cellular effects different from those triggered in cancer cells by DNA adducts of cisplatin. This might lead to the therapeutic effects that could radically improve chemotherapy by platinum complexes. In addition, the findings of the present work make new insights into mechanisms associated with antitumor effects of dinuclear/trinuclear Pt(II) complexes possible.
- MeSH
- bezbuněčný systém MeSH
- DNA chemie MeSH
- fluorescence MeSH
- glutathion chemie MeSH
- konformace nukleové kyseliny MeSH
- molekulární sekvence - údaje MeSH
- oprava DNA MeSH
- organoplatinové sloučeniny farmakologie chemie MeSH
- protinádorové látky farmakologie chemie MeSH
- sekvence nukleotidů MeSH
- síra chemie MeSH
- Publikační typ
- práce podpořená grantem MeSH
The primary objective was to understand more deeply the molecular mechanism underlying different antitumor effects of dinuclear Pt(II) complexes containing aromatic linkers of different length, {[cis-Pt(NH(3))(2)Cl](2)(4,4'-methylenedianiline)}(2+) (1) and {[cis-Pt(NH(3))(2)Cl](2)(alpha,alpha'-diamino-p-xylene)}(2+) (2). These complexes belong to a new generation of promising polynuclear platinum drugs resistant to decomposition by sulfur nucleophiles which hampers clinical use of bifunctional polynuclear trans Pt(II) complexes hitherto tested. Results obtained with the aid of methods of molecular biophysics and pharmacology reveal differences and new details of DNA modifications by 1 and 2 and recognition of these modifications by cellular components. The results indicate that the unique properties of DNA interstrand cross-links of this class of polynuclear platinum complexes and recognition of these cross-links may play a prevalent role in antitumor effects of these metallodrugs. Moreover, the results show for the first time a strong specific recognition and binding of high-mobility-group-domain proteins, which are known to modulate antitumor effects of clinically used platinum drugs, to DNA modified by a polynuclear platinum complex.
- MeSH
- adukty DNA chemie metabolismus MeSH
- cisplatina chemie metabolismus farmakologie MeSH
- HeLa buňky MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- poškození DNA účinky léků fyziologie MeSH
- protinádorové látky chemie metabolismus farmakologie MeSH
- reagencia zkříženě vázaná chemie metabolismus farmakologie MeSH
- viabilita buněk účinky léků fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
