BACKGROUND/AIM: We report the incorporation of prospective anticancer agent hypericin into DNA and bovine serum albumin (BSA), respectively, with emphasis on comparison of the differences in interaction mode between hypericin and its model compound emodin. MATERIALS AND METHODS: Spectrophotometric methods were used for determination of the binding constants of the drug complex with biomacromolecules. Differential scanning calorimetry was applied for evaluation of drug-macromolecule complex thermal stability. RESULTS: The strength of interaction expressed by binding constants was found to be 4.0×104 l/mol for hypericin-DNA and 8.1×104 l/mol for emodin-DNA complex. Both molecules stabilize bovine serum albumin macromolecule and bind into the hydrophobic cavity in IIA subunit but their localization within the molecule is different. CONCLUSION: Anticancer agent hypericin and its derivative emodin interact with DNA with medium strength and are probably incorporated into the groove of DNA by hydrogen bonds. Bovine serum albumin can serve as a transport protein for hypericin since the binding force between both molecules is adequate.
- MeSH
- DNA chemie metabolismus MeSH
- emodin chemie farmakologie MeSH
- molekulární struktura MeSH
- perylen analogy a deriváty chemie farmakologie MeSH
- protinádorové látky chemie farmakologie MeSH
- sérový albumin hovězí chemie metabolismus MeSH
- spektrální analýza MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
By means of fluorescence microscopy the intracellular distribution of fluorescent drugs with different hydrophobicity (quinizarin, emodin and hypericin) was studied. Selective photoactivation of these drugs in precisely defined position (nuclear envelope) allowed moderately hydrophobic emodin enter the nucleus. Highly hydrophobic hypericin was predominantly kept in the membranes with no fluorescence observed in the nucleus. The redistribution of quinizarin, emodin and hypericin between lipids, proteins and DNA was studied in solutions and cells. Based on these results was proposed theoretical model of hydrophobic drugs' nuclear internalization after photo-activation. Molecular docking models showed that hypericin has the strongest affinity to P-glycoprotein involved in the cell detoxification. Presence of 10 μM quinizarin, emodin or hypericin increased P-glycoprotein function in U87 MG cells. Moreover, emodin pretreatment allowed quinizarin nuclear internalization without photo-activation, which was not the case for hypericin. The synergy of such pretreatment and photo-activation should lessen the drug doses with simultaneous increase of drug efficacy triggering cell apoptosis/necrosis.
- MeSH
- anthrachinony chemie farmakologie účinky záření MeSH
- buněčné jádro metabolismus účinky záření MeSH
- DNA chemie MeSH
- emodin chemie farmakologie účinky záření MeSH
- gliom metabolismus MeSH
- hydrofobní a hydrofilní interakce MeSH
- LDL-cholesterol chemie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- P-glykoprotein metabolismus MeSH
- perylen analogy a deriváty chemie farmakologie účinky záření MeSH
- sérový albumin chemie MeSH
- simulace molekulového dockingu MeSH
- světlo MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The clinical application of anthracyclines, like daunorubicin and doxorubicin, is limited by two factors: dose-related cardiotoxicity and drug resistance. Both have been linked to reductive metabolism of the parent drug to their metabolites daunorubicinol and doxorubicinol, respectively. These metabolites show significantly less anti-neoplastic properties as their parent drugs and accumulate in cardiac tissue leading to chronic cardiotoxicity. Therefore, we aimed to identify novel and potent natural inhibitors for anthracycline reductases, which enhance the anticancer effect of anthracyclines by preventing the development of anthracycline resistance. Human enzymes responsible for the reductive metabolism of daunorubicin were tested for their sensitivity towards anthrachinones, in particular emodin and anthraflavic acid. Intense inhibition kinetic data for the most effective daunorubicin reductases, including IC50- and Ki-values, the mode of inhibition, as well as molecular docking, were compiled. Subsequently, a cytotoxicity profile and the ability of emodin to reverse daunorubicin resistance were determined using multiresistant A549 lung cancer and HepG2 liver cancer cells. Emodin potently inhibited the four main human daunorubicin reductases in vitro. Further, we could demonstrate that emodin is able to synergistically sensitize human cancer cells towards daunorubicin at clinically relevant concentrations. Therefore, emodin may yield the potential to enhance the therapeutic effectiveness of anthracyclines by preventing anthracycline resistance via inhibition of the anthracycline reductases. In symphony with its known pharmacological properties, emodin might be a compound of particular interest in the management of anthracycline chemotherapy efficacy and their adverse effects.
- MeSH
- anthrachinony farmakologie MeSH
- chemorezistence účinky léků MeSH
- daunomycin farmakologie MeSH
- emodin farmakologie MeSH
- inhibitory proteinkinas farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- oxidoreduktasy antagonisté a inhibitory metabolismus MeSH
- protinádorová antibiotika farmakologie MeSH
- simulace molekulového dockingu MeSH
- synergismus léků MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of lichen secondary metabolites (parietin, atranorin, usnic and gyrophoric acid) and their interactions with calf thymus DNA were investigated using molecular biophysics and biochemical methods. The binding constants K were estimated to range from 4.3×10(5) to 2.4×10(7)M(-1) and the percentage of hypochromism was found to be 16-34% (from spectral titration). The results of spectral measurement indicate that the compounds act as effective DNA-interacting agents. Electrophoretic separation studies prove that from all the metabolites tested in this study, only gyrophoric acid exhibited an inhibitory effect on Topo I (25μM).
- MeSH
- benzoáty farmakologie MeSH
- benzofurany farmakologie MeSH
- cirkulární dichroismus MeSH
- DNA účinky léků metabolismus MeSH
- emodin analogy a deriváty farmakologie MeSH
- hydroxybenzoáty farmakologie MeSH
- inhibitory topoisomerasy I farmakologie MeSH
- inhibitory topoisomerasy II farmakologie MeSH
- interkalátory farmakologie MeSH
- kinetika MeSH
- konformace nukleové kyseliny MeSH
- lidé MeSH
- lišejníky chemie metabolismus MeSH
- skot MeSH
- spektrofotometrie ultrafialová MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Fallopia japonica and its hybrid, F. xbohemica, due to their fast spread, are famous as nature threats rather than blessings. Their fast growth rate, height, coverage, efficient nutrient translocation between tillers and organs and high phenolic production, may be perceived either as dangerous or beneficial features that bring about the elimination of native species or a life-supporting source. To the best of our knowledge, there have not been any studies aimed at increasing the targeted production of medically desired compounds by these remarkable plants. We designed a two-year pot experiment to determine the extent to which stilbene (resveratrol, piceatannol, resveratrolosid, piceid and astringins) and emodin contents of F. japonica, F. sachalinensis and two selected F. xbohemica clones are affected by soil nitrogen (N) supply, leaf damage and mycorrhizal inoculation. RESULTS: 1) Knotweeds are able to grow on substrates with extremely low nitrogen content and have a high efficiency of N translocation. The fast-spreading hybrid clones store less N in their rhizomes than the parental species. 2) The highest concentrations of stilbenes were found in the belowground biomass of F. japonica. However, because of the high belowground biomass of one clone of F. xbohemica, this hybrid produced more stilbenes per plant than F. japonica. 3) Leaf damage increased the resveratrol and emodin contents in the belowground biomass of the non-inoculated knotweed plants. 4) Although knotweed is supposed to be a non-mycorrhizal species, its roots are able to host the fungi. Inoculation with mycorrhizal fungi resulted in up to 2% root colonisation. 5) Both leaf damage and inoculation with mycorrhizal fungi elicited an increase of the piceid (resveratrol-glucoside) content in the belowground biomass of F. japonica. However, the mycorrhizal fungi only elicited this response in the absence of leaf damage. Because the leaf damage suppressed the effect of the root fungi, the effect of leaf damage prevailed over the effect of the mycorrhizal fungi on the piceid content in the belowground biomass. CONCLUSIONS: Two widely spread knotweed species, F. japonica and F. xbohemica, are promising sources of compounds that may have a positive impact on human health. The content of some of the target compounds in the plant tissues can be significantly altered by the cultivation conditions including stress imposed on the plants, inoculation with mycorrhizal fungi and selection of the appropriate plant clone.
- MeSH
- biomasa MeSH
- dusík metabolismus MeSH
- emodin metabolismus MeSH
- listy rostlin chemie účinky léků MeSH
- mykorhiza růst a vývoj MeSH
- oddenek chemie mikrobiologie MeSH
- Polygonum chemie růst a vývoj mikrobiologie MeSH
- průmyslová hnojiva MeSH
- půda chemie MeSH
- roční období MeSH
- stilbeny metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Japanese knotweed, Reynoutria japonica, is known for its high growth rate, even on adverse substrates, and for containing organic substances that are beneficial to human health. Its hybrid, Reynoutria x bohemica, was described in the Czech Republic in 1983 and has been widespread ever since. We examined whether Reynoutria x bohemica as a medicinal plant providing stilbenes and emodin, can be cultivated in spoil bank substrates and hence in the coalmine spoil banks changed into arable fields. We designed a pot experiment and a field experiment to assess the effects of various factors on the growth efficiency of Reynoutria x bohemica on clayish substrates and on the production of stilbenes and emodin in this plant. RESULTS: In the pot experiment, plants were grown on different substrates that varied in organic matter and nutrient content, namely the content of nitrogen and phosphorus. Nitrogen was also introduced into the substrates by melilot, a leguminous plant with nitrogen-fixing rhizobia. Melilot served as a donor of mycorrhizal fungi to knotweed, which did not form any mycorrhiza when grown alone. As expected, the production of knotweed biomass was highest on high-nutrient substrates, namely compost. However, the concentration of the organic constituents studied was higher in plants grown on clayish low-nutrient substrates in the presence of melilot. The content of resveratrol including that of its derivatives, resveratrolosid, piceatannol, piceid and astringin, was significantly higher in the presence of melilot on clay, loess and clayCS. Nitrogen supplied to knotweed by melilot was correlated with the ratio of resveratrol to resveratrol glucosides, indicating that knotweed bestowed some of its glucose production upon covering part of the energy demanded for nitrogen fixation by melilot's rhizobia, and that there is an exchange of organic substances between these two plant species. The three-year field experiment confirmed the ability of Reynoutria x bohemica to grow on vast coalmine spoil banks. The production of this species reached 2.6 t of dry mass per hectare. CONCLUSIONS: Relationships between nitrogen, phosphorus, emodin, and belowground knotweed biomass belong to the most interesting results of this study. Compared with melilot absence, its presence increased the number of significant relationships by introducing those of resveratrol and its derivatives, and phosphorus and nitrogen. Knotweed phosphorus was predominantly taken up from the substrate and was negatively correlated with the content of resveratrol and resveratrol derivatives, while knotweed nitrogen was mainly supplied by melilot rhizobia and was positively correlated with the content of resveratrol and resveratrol derivatives.
- MeSH
- biomasa MeSH
- dusík metabolismus MeSH
- emodin metabolismus MeSH
- fosfor metabolismus MeSH
- léčivé rostliny chemie růst a vývoj mikrobiologie MeSH
- mykorhiza růst a vývoj MeSH
- Polygonum chemie růst a vývoj mikrobiologie MeSH
- půda analýza MeSH
- stilbeny metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
