The adverse side effects and acquired resistance associated with the clinical application of traditional platinum-based anticancer drugs have forced investigation of alternative transition metal-based compounds and their cytostatic properties. Over the last years, the anticancer potential of cobalt complexes has been extensively studied, and in-depth analyses of their mode of action have been conducted. In this work, we present antiproliferative activity against human cancer cells of the dinuclear Co(III) complexes bearing the quinizarin ligand and tris(2-aminoethyl)amine (tren, compound 1) or tris(2-pyridylmethyl)amine (tpa, compound 2) co-ligands. To contribute the understanding mechanisms of biological action of these compounds, their association with DNA in the cells, DNA binding in cell-free media, and DNA cleavage capability were investigated in detail. The results demonstrate that both complexes interact with DNA in tumor cells. However, their mechanism of antiproliferative action is different, and this difference is mirrored by distinct antiproliferative activity. The antiproliferative effect of 1 is connected with its ability to intercalate into DNA and subsequently to inhibit activities of DNA processing enzymes. In contrast, the total antiproliferative efficiency of 2, thanks to its redox properties, appears to be connected with its ability to form radicals and, consequently, with the ability of 2 to cleave DNA. Hence, the findings presented in this study may significantly contribute to understanding the antitumor potential of cobalt complexes. Dinuclear Co(III) complexes containing the bioactive quinizarin ligand exhibit antiproliferative activity based on distinct mechanism.
- MeSH
- anthrachinony chemie farmakologie MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- DNA chemie MeSH
- kobalt chemie farmakologie MeSH
- komplexní sloučeniny chemická syntéza chemie farmakologie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- ligandy MeSH
- molekulární konformace MeSH
- nádorové buňky kultivované MeSH
- proliferace buněk účinky léků MeSH
- štěpení DNA MeSH
- vazebná místa účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Russula atropurpurea can accumulate remarkably high concentrations of Zn in its sporocarps. We have previously demonstrated that 40 % of the intracellular Zn in this species is sequestered by MT-like RaZBP peptides. To see what other mechanisms for the handling of the accumulated Zn are available to R. atropurpurea, we searched its transcriptome for cDNAs coding for transporters of the cation diffusion facilitator (CDF) family. The transcriptome search enabled us to identify RaCDF1 and RaCDF2, which were further subjected to functional studies in metal sensitive Saccharomyces cerevisiae. The expression of RaCDF1 and its translational fusion with green fluorescent protein (GFP) protected the yeasts against Zn and Co, but not Cd or Mn, toxicity and led to increased Zn accumulation in the cells. The GFP fluorescence, observed in the RaCDF1::GFP-expressing yeasts on tonoplasts, indicated that the RaCDF1-mediated Zn and Co tolerance was a result of vacuolar sequestration of the metals. The expression of RaCDF2 supported Zn, but not Mn, tolerance in the yeasts and reduced the cellular uptake of Zn, which is congruent with the proposed idea of the Zn-efflux function of RaCDF2, supported by the localization of GFP-derived fluorescence on the plasma membrane of the yeasts expressing functional RaCDF2::GFP. Contrarily, RaCDF2 increased the sensitivity to Co and Cd in the yeasts and significantly promoted Cd uptake, which suggested that it can act as a bidirectional metal transporter. The notion that RaCDF1 and RaCDF2 are genuine CDF transporters in R. atropurputrea was further reinforced by the fact that the RaCDF-associated metal tolerance and uptake phenotypes were lost upon the replacement of histidyl (in RaCDF1) and aspartyl (in RaCDF2), which are highly conserved in the second transmembrane domain and known to be essential for the function of CDF proteins.
- MeSH
- aktivace transkripce MeSH
- antifungální látky farmakologie MeSH
- fungální proteiny chemie genetika metabolismus MeSH
- fyziologická adaptace MeSH
- geny hub MeSH
- kobalt farmakologie MeSH
- membránové transportní proteiny chemie genetika metabolismus MeSH
- mikrobiální testy citlivosti MeSH
- mikrobiální viabilita MeSH
- mykorhiza genetika metabolismus MeSH
- regulace genové exprese u hub MeSH
- Saccharomyces cerevisiae účinky léků růst a vývoj MeSH
- sekvence aminokyselin MeSH
- zinek metabolismus farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Metal-based coordination compounds have been used throughout the history of human medicine to treat various diseases, including cancer. Since the discovery of cisplatin in 1965, a great number of metal coordination complexes, such as platinum, ruthenium, gold or copper have been designed, synthesized and tested in order to develop clinically effective and safe drugs. Currently, many reviews cover applications of cytostatic metal complexes pointing out the most promising examples of platinum- and non-platinum-based compounds in preclinical and clinical trials. However, recent comprehensive reviews covering chemical and biological aspects of metal-based coordination compounds in cancer therapy are still rare. In this review we wish to provide an overview of the coordination chemistry of current and novel cytostatic compounds, including an outline of their design and rationale of synthesis, and summarize bio-chemical reactivity and physicochemical properties of candidate metal complexes.
- MeSH
- antitumorózní látky * farmakologie terapeutické užití MeSH
- cisplatina dějiny farmakologie terapeutické užití MeSH
- galium dějiny farmakologie terapeutické užití MeSH
- genomika metody trendy MeSH
- individualizovaná medicína metody trendy využití MeSH
- kobalt dějiny farmakologie terapeutické užití MeSH
- komplexní sloučeniny * farmakologie terapeutické užití MeSH
- lidé MeSH
- měď farmakologie terapeutické užití MeSH
- metabolomika metody trendy MeSH
- mezioborová komunikace MeSH
- proteomika metody trendy MeSH
- sloučeniny ruthenia dějiny farmakologie terapeutické užití MeSH
- sloučeniny železa dějiny farmakologie terapeutické užití MeSH
- sloučeniny zlata dějiny farmakologie terapeutické užití MeSH
- statistika jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Metallacarborane moieties have been identified as promising pharmacophores. The pharmaceutical use of such compounds is, however, complicated by their low solubility and tendency to self-assemble in aqueous solution. In this work, we estimated the solubilities of a vast series of metallacarboranes [cobalt bis(dicarbollide) derivatives] in pure water, saline, and saline with human serum albumin as a model of blood plasma. In addition, we determined the octanol-water partition coefficients (Pow) as a lipophilicity descriptor. Pow weakly correlates with the water solubility of metallacarboranes, whereas the ability of HSA to increase the solubility of metallacarboranes correlates well with their Pow values. Because metallacarboranes are known inhibitors of HIV protease, the possible correlation between Pow and the ability to inhibit HIV protease was investigated. Results from this study indicate that interaction of metallacarborane inhibitors with HIV protease is driven by specific binding rather than by promiscuous lipophilic interactions. The most promising candidates for further drug development were identified by ligand lipophilicity efficiency analysis.
- MeSH
- inhibitory HIV-proteasy chemie farmakologie MeSH
- kobalt chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- lipidy chemie MeSH
- molekulární struktura MeSH
- objevování léků MeSH
- organokovové sloučeniny chemie farmakologie MeSH
- rozpustnost MeSH
- sérový albumin chemie MeSH
- sloučeniny boru chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A decrease in oxidative phosphorylation (OXPHOS) is characteristic of many cancer types and, in particular, of clear cell renal carcinoma (CCRC) deficient in von Hippel-Lindau (vhl) gene. In the absence of functional pVHL, hypoxia-inducible factor (HIF) 1-alpha and HIF2-alpha subunits are stabilized, which induces the transcription of many genes including those involved in glycolysis and reactive oxygen species (ROS) metabolism. Transfection of these cells with vhl is known to restore HIF-alpha subunit degradation and to reduce glycolytic genes transcription. We show that such transfection with vhl of 786-0 CCRC (which are devoid of HIF1-alpha) also increased the content of respiratory chain subunits. However, the levels of most transcripts encoding OXPHOS subunits were not modified. Inhibition of HIF2-alpha synthesis by RNA interference in pVHL-deficient 786-0 CCRC also restored respiratory chain subunit content and clearly demonstrated a key role of HIF in OXPHOS regulation. In agreement with these observations, stabilization of HIF-alpha subunit by CoCl(2) decreased respiratory chain subunit levels in CCRC cells expressing pVHL. In addition, HIF stimulated ROS production and mitochondrial manganese superoxide dismutase content. OXPHOS subunit content was also decreased by added H(2)O(2.) Interestingly, desferrioxamine (DFO) that also stabilized HIF did not decrease respiratory chain subunit level. While CoCl(2) significantly stimulates ROS production, DFO is known to prevent hydroxyl radical production by inhibiting Fenton reactions. This indicates that the HIF-induced decrease in OXPHOS is at least in part mediated by hydroxyl radical production.
- MeSH
- deferoxamin farmakologie MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa * genetika metabolismus MeSH
- glykolýza genetika MeSH
- homeostáza MeSH
- kobalt farmakologie MeSH
- lidé MeSH
- nádory genetika MeSH
- oxidativní fosforylace * MeSH
- peroxid vodíku farmakologie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- reaktivní formy kyslíku * metabolismus MeSH
- receptory aromatických uhlovodíků - jaderný translokátor * genetika metabolismus MeSH
- respirační vzplanutí fyziologie účinky léků MeSH
- sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
- transportní proteiny genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- chromatografie na tenké vrstvě metody přístrojové vybavení využití MeSH
- difenylamin analogy a deriváty farmakologie chemie MeSH
- dusitan sodný chemie MeSH
- farmaceutická technologie metody přístrojové vybavení MeSH
- fenoly farmakologie chemie izolace a purifikace MeSH
- fenothiaziny analýza farmakologie chemie MeSH
- indikátory a reagencie chemie MeSH
- kobalt farmakologie chemie MeSH
- spektrofotometrie metody přístrojové vybavení využití MeSH
- trimeprazin farmakologie chemie MeSH
Rostlinná buÀka reaguje na zv˘‰enou koncentraci kovÛ v prostfiedí rÛzn˘mi mechanizmy. Patfií mezi nû zv˘‰ení tvorby proteinÛ tepelného ‰oku, metalothioneinÛ, fytochelatinÛ, aminokyselin (cysteinu, histidinu), organick˘ch kyselin (citronové, jableãné) nebo sekundárních metabolitÛ. Poslední mechanizmus je zkoumán pro moÏnost vyuÏití v explantátov˘ch kulturách ke stimulaci sekundárního metabolizmu, kter˘ je zdrojem farmaceuticky v˘znamn˘ch látek. V práci byly testovány manganaté (0; 0,1; 0,2; 0,5; 1; 2; 5; 10; 20 a 50 mM/l média), kobaltnaté a nikelnaté ionty (0; 0,1; 0,5; 1; 5; 10; 50; 100; 200 a 500 μM/l média) jako potenciální elicitory produkce kumarinÛ. Souãasnû byla sledována toxicita tûchto kovÛ pro kulturu hodnocením vlivu na rÛst (charakterizován ãerstvou a suchou hmotností biomasy na konci ãtrnáctidenní kultivace). Kultury byly kultivovány ve tmû a na svûtle. Bylo zji‰tûno, Ïe rÛst kultur není ovlivnûn manganem v koncentracích 0 aÏ 2 mM, poté mírnû klesá, pfii koncentraci 50 mM je o 20 % niωí pfii kultivaci ve tmû a o 30 % pfii kultivaci na svûtle ve srovnání s kontrolou. Kobalt v koncentracích 0 aÏ 50 μM neovlivÀuje v˘znamnû rÛst kultury, vy‰‰í koncentrace sniÏují nárÛst biomasy, v˘raznûji pfii kultivaci na svûtle (pfii 500 μM Co o 60 %, ve tmû jen o 30 % ve srovnání s kontrolami). Nikl v koncentracích 0,1 aÏ 200 μM neovlivÀuje rÛst, v koncentraci 500 μM jej sniÏuje pfiibliÏnû o 30 % ve srovnání s kontrolou pfii kultivaci na svûtle i ve tmû. Produkce kumarinÛ nebyla Ïádn˘m kovem stimulována v porovnání s kontrolními kulturami. Pouze odstranûní manganu z média v kultufie kultivované ve tmû zv˘‰ilo produkci asi o 15 % oproti kontrole.
The plant cell reacts to an increased concentration of metals in the environment by various mechanisms. They include an increase in the formation of heat-shock proteins, metallothioneins, phytochelatins, amino acids (cysteine, histidine), organic acids (citric, malic), or secondary metabolites. The latter mechanism is being investigated for its possible use in explant cultures for the stimulation of secondary metabolism, which is the source of substances of pharmaceutical importance. The study tested manganese (II) (0, 0.1, 0.2, 0.5, 1, 2, 5, 10, 20, and 50 mM in the medium), cobalt (II), and nickel (II) ions (0, 0.1, 0.5, 1, 5, 10, 50, 100, 200, and 500 μM in the medium) as potential elicitors of coumarin production. At the same time, toxicity of these metals for the culture was examined by evaluating their effect on growth (characterized by fresh and dry weight of biomass at the end of a two-week cultivation). Cultures were cultivated in the dark and in the light. It has been found that the growth of cultures is not influenced by manganese in concentrations ranging from 0 to 2 mM, then it slightly decreases, at a concentration of 50 mM it is lower by 20 % when cultivated in the dark and by 30 % when cultivated in the light in comparison with the control. Cobalt in concentrations of 0 to 50 μM does not significantly influence the growth of the culture, higher concentrations decrease the biomass yields, more markedly when cultivated in the light (at 500 μM Co by 60 %, in the dark only by 30 % in comparison with the controls). Nickel in concentrations of 0.1 to 200 μM does not influence growth, and in a concentration of 500 μM decreases it by approximately 30 % in comparison with the control both in the light and dark. Production of coumarins was not stimulated by any metal in comparison with the control cultures, only the remo- val of manganese from the medium in the culture cultivated in the dark increased production by about 15 % versus the control.
Erythropoietin (EPO) is a factor essential for erythroid cell proliferation, differentiation, and survival. The production of EPO by the kidneys in response to hypoxia and anemia is well documented. To determine whether EPO is also produced by hematopoietic cells, we analyzed the expression of EPO in normal human hematopoietic progenitors and in their progeny. Undifferentiated CD34(+)lin- hematopoietic progenitors do not have detectable EPO mRNA. Differentiating CD34(+) cells that are stimulated with recombinant human EPO in serum-free liquid cultures express both EPO and EPO receptor (EPOR). Because CD34(+) cells represent a heterogeneous cell population, we analyzed individual burst-forming units-erythroid (BFU-E) and nonerythroid colony-forming unit-granulocyte-macrophage colonies for EPO mRNA. Only BFU-E colonies were positive for EPO mRNA. Lysates from pooled BFU-E colonies stained positively for EPO by immunoblotting. To further confirm the intrinsic nature of erythroid EPO, we replaced extrinsic EPO in erythroid colony cultures with EPO-mimicking peptide (EMP). We show EPO expression in the EMP-stimulated BFU-Es at both mRNA and protein levels. Stimulation of bone marrow mononuclear cells (BMMCs) with EMP upregulated EPO expression. Furthermore, we found EPO and EPOR mRNAs as well as EPO protein in K562 cells, a human erythroleukemia cell line. Stimulation of K562 cells with EMP upregulated EPO expression. We suggest that EPO of erythroid origin may have a role in the regulation of erythropoiesis.
- MeSH
- akutní erytroblastická leukemie patologie MeSH
- antigeny CD34 analýza MeSH
- chronická myeloidní leukemie patologie MeSH
- dospělí MeSH
- ELISA MeSH
- erythropoetin biosyntéza genetika MeSH
- erytroidní prekurzorové buňky metabolismus účinky léků MeSH
- erytropoéza genetika účinky léků MeSH
- hematopoetické kmenové buňky metabolismus účinky léků MeSH
- hepatocelulární karcinom patologie MeSH
- hypoxie buňky genetika MeSH
- kobalt farmakologie MeSH
- kultivační média bez séra MeSH
- kultivované buňky MeSH
- lidé MeSH
- messenger RNA biosyntéza MeSH
- molekulární sekvence - údaje MeSH
- nádorové buňky kultivované MeSH
- nádory jater patologie MeSH
- peptidy farmakologie MeSH
- receptory erythropoetinu biosyntéza genetika MeSH
- regulace genové exprese MeSH
- sekvence nukleotidů MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
