A structure-activity relationship (SAR) study in terms of G-quadruplex binding ability and antiproliferative activity of six fluorescent perylenemonoimide (PMIs) derivatives is reported. A positive charge seems to be the key to target G4. This study also reveals the importance of the element substitution in the potential biological activity of PMIs, being the polyethylene glycol (PEG) chains in the peri position responsible for their antiproliferative activity. Among them, the cationic PMI6 with two PEG chains is the most promising compound since its fluorescence is enhanced in the presence of G-quadruplex structures. Moreover, PMI6 binds to the human telomeric G-quadruplex hTelo with high affinity and displays a high antiproliferative potential towards HeLa (cervical adenocarcinoma), A549 (lung adenocarcinoma) and A2780 (ovarian adenocarcinoma) cells. Its fate can be followed inside cells thanks to its fluorescent properties: the compound is found to accumulate in the mitochondria.
- MeSH
- G-kvadruplexy účinky léků MeSH
- imidy chemická syntéza chemie farmakologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- mitochondrie účinky léků MeSH
- molekulární struktura MeSH
- perylen analogy a deriváty chemická syntéza chemie farmakologie MeSH
- proliferace buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Photosensitive compounds found in herbs have been reported in recent years as having a variety of interesting medicinal and biological activities. In this review, we focus on photosensitizers such as hypericin and its model compounds emodin, quinizarin, and danthron, which have antiviral, antifungal, antineoplastic, and antitumor effects. They can be utilized as potential agents in photodynamic therapy, especially in photodynamic therapy (PDT) for cancer. We aimed to give a comprehensive summary of the physical and chemical properties of these interesting molecules, emphasizing their mechanism of action in relation to their different interactions with biomacromolecules, specifically with DNA.
- MeSH
- anthrachinony chemie MeSH
- fotochemoterapie MeSH
- fotosenzibilizující látky chemie farmakologie MeSH
- lidé MeSH
- nádory farmakoterapie MeSH
- perylen analogy a deriváty chemie farmakologie MeSH
- protinádorové látky chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
OBJECTIVE: Cancer stem-like cells (CSLCs) are considered a root of tumorigenicity and resistance. However, their identification remains challenging. The use of the side population (SP) assay as a credible marker of CSLCs remains controversial. The SP assay relies on the elevated activity of ABC transporters that, in turn, can be modulated by hypericin (HYP), a photosensitizer and bioactive compound of St. John's Wort (Hypericum perforatum), a popular over-the-counter antidepressant. Here we aimed to comprehensively characterize the SP phenotype of cancer cells and to determine the impact of HYP on these cells. METHODS: Flow cytometry and sorting-based assays were employed, including CD24-, CD44-, CD133-, and ALDH-positivity, clonogenicity, 3D-forming ability, ABC transporter expression and activity, and intracellular accumulation of HYP/Hoechst 33342. The tumorigenic ability of SP, nonSP, and HYP-treated cells was verified by xenotransplantation into immunodeficient mice. RESULTS: The SP phenotype was associated with elevated expression of several investigated transporters and more intensive growth in non-adherent conditions but not with higher clonogenicity, tumorigenicity or ALDH-positivity. Despite stimulated BCRP level and MRP1 activity, HYP reversibly decreased the SP proportion, presumably via competitive inhibition of BCRP. HYP-selected SP cells acquired additional traits of resistance and extensively eliminated HYP. CONCLUSIONS: Our results suggest that SP is not an unequivocal CSLC-marker. However, SP could play an important role in modulating HYP-treatment and serve as a negative predictive tool for HYP-based therapies. Moreover, the use of supplements containing HYP by cancer patients should be carefully considered, due to its proposed effect on drug efflux and complex impact on tumor cells, which have not yet been sufficiently characterized.
- MeSH
- ABC transportér z rodiny G, člen 2 metabolismus MeSH
- aldehyddehydrogenasa metabolismus MeSH
- analýza přežití MeSH
- buněčné klony MeSH
- buněčné sféroidy účinky léků metabolismus patologie MeSH
- fenotyp MeSH
- karcinogeneze účinky léků metabolismus patologie MeSH
- lidé MeSH
- myši SCID MeSH
- nádorové biomarkery metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky účinky léků metabolismus patologie MeSH
- nádorové proteiny metabolismus MeSH
- nádory metabolismus patologie MeSH
- P-glykoprotein metabolismus MeSH
- perylen analogy a deriváty farmakologie MeSH
- substrátová specifita účinky léků MeSH
- vedlejší populace buněk účinky léků patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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
This article is directed to determining concentrations of polycyclic aromatic hydrocarbons (PAHs), which are sorbed to solid particles in the air. Pollution sources were identified on the basis of the ratio of benzo[ghi]perylene (BghiPe) to benzo[a]pyrene (BaP). Because various important information is lost by determining the simple ratio of concentrations, least squares linear regression (classic ordinary least squares regression), reduced major axis, orthogonal regression, and Kendall-Theil robust diagnostics were utilized for identification. Statistical evaluation using all aforementioned methods demonstrated different ratios of the monitored PAHs in the intervals examined during warmer and colder periods. Analogous outputs were provided by comparing gradients of the emission factors acquired from the measured concentrations of BghiPe and BaP in motor vehicle exhaust gases. Based on these outputs, it was possible plausibly to state that the influence of burning organic fuels in heating stoves is prevalent in colder periods whereas in warmer periods transport was the exclusive source because other sources of PAH emissions were not found in the examined locations.
- MeSH
- benzopyren analýza MeSH
- hodnocení rizik MeSH
- látky znečišťující vzduch analýza MeSH
- lineární modely MeSH
- metoda nejmenších čtverců MeSH
- monitorování životního prostředí metody statistika a číselné údaje MeSH
- perylen analogy a deriváty analýza MeSH
- pevné částice analýza MeSH
- polycyklické aromatické uhlovodíky analýza MeSH
- roční období MeSH
- urbanizace MeSH
- výfukové emise vozidel analýza MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika 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
By means of fluorescence spectroscopy we have studied the kinetics of interaction of a photosensitizer hypericin (Hyp) with high-density lipoproteins (HDL). Hyp is incorporated into HDL molecules as monomer till ratio Hyp/HDL ∼8:1 and above this ratio forms non-fluorescent aggregates. This number is different from that found in the case of Hyp incorporation into low-density lipoprotein (LDL) molecules (8:1 vs 30:1). The difference is mainly attributed to the smaller size of HDL in comparison with LDL molecule. Biphasic kinetics of Hyp association with HDL was observed. The rapid phase of incorporation is completed within seconds, while the slow one lasts several minutes. The kinetics of the association of Hyp molecules with free HDL, Hyp/HDL=10:1 complex and the redistribution of Hyp from Hyp/HDL=70:1 complex to free HDL molecules reveal a qualitative similar characteristics of these processes with those observed for the interaction of Hyp with LDL. However, the incorporation of Hyp into HDL in the "slow" phase is more rapid than to LDL and extend of Hyp penetration into lipoproteins in the fast phase is also much higher in the case of HDL. The lower concentration of cholesterol molecules in outer shell of HDL particles is probably the determining factor for the more rapid kinetics of Hyp incorporation to and redistribution from these molecules when comparing with LDL particles.
- MeSH
- buněčné linie MeSH
- farmaceutická chemie MeSH
- fluorescenční spektrometrie MeSH
- fotosenzibilizující látky chemie MeSH
- lipoproteiny HDL chemie MeSH
- lipoproteiny LDL chemie MeSH
- perylen analogy a deriváty chemie MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Some endophyte isolates were isolated in a bamboo pole sample parasitized the fungus Shiraia bambusicola from Zhejiang Province. After screening through hypocrellin bacteriostatic effect and fermentation test, we got the isolate TX4 of bacterial elicitor and GZUIFR-TT1 of fungal elicitor which had certain effect to promote S. bambusicola to produce hypocrellin. The Plackett-Burman design was introduced to evaluate the effects of nine factors based on single-factor test. Yeast extract, glucose, and isolate GZUIFR-TT1 elicitor were found to be the critical activity factors for increasing the total hypocrellin production. So we identified the isolate GZUIFR-TT1 as Trametes sp. Through response surface methodology, we obtained the optimum production conditions as follows: yeast extract, 2.99 g/L; glucose, 32.45 g/L; and Trametes sp. elicitor, 81.40 μg/mL. Under the above conditions, the experimental value of hypocrellin production was 102.60 mg/L, compared with the control it increased about 7.90 times.
- MeSH
- antiinfekční látky metabolismus MeSH
- Ascomycota metabolismus MeSH
- biotechnologie metody MeSH
- chinony metabolismus MeSH
- DNA fungální chemie genetika MeSH
- fermentace MeSH
- kultivační média chemie MeSH
- mezerníky ribozomální DNA chemie genetika MeSH
- molekulární sekvence - údaje MeSH
- perylen analogy a deriváty metabolismus MeSH
- sekvenční analýza DNA MeSH
- Trametes klasifikace genetika růst a vývoj izolace a purifikace MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- analýza buněčné migrace metody využití MeSH
- biomedicínský výzkum MeSH
- chalkon analogy a deriváty aplikace a dávkování terapeutické užití MeSH
- cytotoxické testy imunologické metody využití MeSH
- endoteliální buňky pupečníkové žíly (lidské) * cytologie enzymologie MeSH
- fotochemoterapie metody využití MeSH
- indikátory a reagencie MeSH
- inhibitory angiogeneze * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- perylen analogy a deriváty aplikace a dávkování terapeutické užití MeSH
- protinádorové látky * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- statistika jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Hypericin, the photoactive compound of Hypericum perforatum, is probably the most powerful photosensitizer found in nature. This compound has shown high potency in the photodynamic treatment of tumor cells. However, there is only limited knowledge regarding the photodynamic effect of hypericin on nonmelanoma skin cancer cells. The aim of this prospective study was to investigate the efficacy of photodynamic therapy with topical application of an extract of H. perforatum in actinic keratosis, basal cell carcinoma (BCC) and morbus Bowen (carcinoma in situ). The study was carried out on 34 patients--eight with actinic keratoses (AKs), 21 with BCC and five with Bowen's disease. The extract of H. perforatum was applied on the skin lesions under occlusion and that was followed by irradiation with 75 J cm(-2) of red light 2 h later. The treatment was performed weekly for 6 weeks on average. The percentage of complete clinical response was 50% for AKs, 28% in patients with superficial BCC and 40% in patients with Bowen's disease. There was only a partial remission seen in patients with nodular BCCs. A complete disappearance of tumor cells was found in the histologic preparation of 11% of patients with superficial BCCs and 80% in the patients with Bowen's disease. All patients complained of burning and pain sensations during irradiation. Although the results of this first clinical trial could be regarded as disappointing, there are still possibilities for improvement. Better preparation of the lesions, enhancement of hypericin delivery and other types of light exposure procedures could significantly improve the clinical outcomes of this relatively inexpensive treatment modality.
- MeSH
- aplikace lokální MeSH
- bazocelulární karcinom farmakoterapie MeSH
- Bowenova nemoc farmakoterapie MeSH
- dospělí MeSH
- financování organizované MeSH
- fotochemoterapie metody MeSH
- fytoterapie MeSH
- keratóza farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádory kůže farmakoterapie MeSH
- perylen analogy a deriváty terapeutické užití MeSH
- pilotní projekty MeSH
- protinádorové látky terapeutické užití MeSH
- rostlinné přípravky terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- třezalka chemie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- klinické zkoušky MeSH
