BackgroundDoxorubicin (Dox) is one of the most potent anticancer drugs, but its successful use is hampered by high toxicity caused mainly by generation of reactive oxygen species. One approach to protect against Dox-dependent chemical insult is combined use of the cytostatic drug with antioxidants. C60 fullerene has a nanostructure with both antioxidant and antitumor potential and may be useful in modulating cell responses to Dox.ObjectiveThe aim of this study was to estimate the antitumor effect and antioxidant enzyme activity of combined C60 fullerene and Dox (C60 + Dox) in the liver and heart of mice with Lewis lung carcinoma compared with Dox treatment alone.MethodsHighly stable pristine C60 fullerene aqueous colloid solution (concentration 1.0 mg/ml, average hydrodynamic diameter of nanoparticles 50 nm) was used in the study and characterized by means of atomic force microscopy (AFM). The in vivo investigation of C60-Dox action was performed via the standard methods of histological and enzyme activity analyses.ResultsDox (total dose 2.5 mg/kg) combined with C60 fullerene (total dose 25 mg/kg) in tumor-bearing animals resulted in tumor growth inhibition, prolongation of life, metastasis inhibition, and increased number of apoptotic tumor cells and was more effective than the corresponding course of Dox treatment alone. C60 fullerene demonstrated a protective effect against superoxide dismutase and glutathione peroxidase inhibition induced by Dox-dependent oxidative insult in the liver and heart.ConclusionCombined treatment with C60 + Dox is considered to be a promising approach for cancer chemotherapy.
In a model experiment on T-cells isolated from Wistar rat thymus the biological activity of nonmodified fullerenes (C 60 ) and multiwalled carbon nanotubes (MWCNT) is studied. It is demonstrated that C 60 at a concentration of 14.4 lg/ml in the cell incubation medium inhibit the activity of plasma membrane Ca 2+ -stimulated ectoATPase. Both, the initial rate of the extracellular ATP hydrolysis and the time of reaching the half-maximum level of the enzyme activity are decreased, while MWCNT (12.5 and 25 lg/ml) have no effect on the kinetic parameters of the ecto-ATPase reaction. It is shown that both C 60 and MWCNT demonstrate a protective effect against H 2 O 2 -induced injury of thymic T-cells.Key words: fullerenes C 60 , carbon nanotubes, thymocytes, ectoATPase, apoptosis, hydrogen peroxide.In einem Modellexperiment an T-Zellen, welche aus Wistar Raten-Thymus gewonnen wurden, wurde die biologische Aktivität von nichtmodifiziertem Fulleren (C 60 ) und von mehrwandigen Carbon-Nanotubes (MWCNT) untersucht. Es konnte gezeigt werde, dass C 60 in einer Konzentration von 14,4 lg/ml im Zellinkubationsmedium die Aktivität der Plasmamembran Ca 2+ -stimulierten ectoATPase inhibiert und sowohl die Ausgangrate der extrazellularen Hydrolyse als auch die Zeit zum Erreichen der des Halb-Maximum-Levels der Enzymaktivität verringert, während MWCNT (Konzentration 12,5 and 25 lg/ml) keinen Effekt auf die kinetischen Parameter der ecto-ATPase Reaktion zeigten. Sowohl Fullerene als auch MWCNT zeigten einen schützenden Effekt gegenüber H 2 O 2 induzierten Störungen in Thymus T-Zellen.
Growth experiments of transplanted malignant tumors in the presence of water-soluble C60 fullerenes were performed on groups of mice. It was found that C60 fullerenes efficiently inhibit the growth of transplanted malignant tumors. This behavior can be explained through their high antioxidant activity and the blocking of the specific cell receptors (for example, endothelial growth factor). The findings demonstrate the possibility of using C60 fullerenes in anticancer therapy.
Fullerene C60 as a representative of carbon nanocompounds is suggested to be promising agent for application in photodynamic therapy due to its unique physicochemical properties. The goal of this study was to estimate the accumulation of fullerene C60 in leukemic cells and to investigate its phototoxic effect on parental and resistant to cisplatin leukemic cells. Stable homogeneous water colloid solution of pristine C60 with average 50-nm diameter of nanoparticles was used in experiments. Fluorescent labeled C60 was synthesized by covalent conjugation of C60 with rhodamine B isothiocyanate. The results of confocal microscopy showed that leukemic Jurkat cells could effectively uptake fullerene C60 from the medium. Light-emitting diode lamp (100 mW cm−2, λ = 420–700 nm) was used for excitation of accumulated C60. A time-dependent decrease of viability was detected when leukemic Jurkat cells were exposed to combined treatment with C60 and visible light. The cytotoxic effect of photoexcited C60 was comparable with that induced by H2O2, as both agents caused 50% decrease of cell viability at 24 h at concentrations about 50 μM. Using immunoblot analysis, protein phosphotyrosine levels in cells were estimated. Combined action of C60 and visible light was followed by decrease of cellular proteins phosphorylation on tyrosine residues though less intensive as compared with that induced by H2O2 or protein tyrosine kinase inhibitor staurosporine. All tested agents reduced phosphorylation of 55, 70, and 90 kDa proteins while total suppression of 26 kDa protein phosphorylation was specific only for photoexcited C60.The cytotoxic effect of C60 in combination with visible light irradiation was demonstrated also on leukemic L1210 cells both sensitive and resistant to cisplatin. It was shown that relative value of mitochondrial membrane potential measured with tetramethylrhodamine ethyl ester perchlorate (TMRE) probe was lower in resistant cells in comparison with sensitive cells and the drop of mitochondrial potential corresponded to further decrease of resistant cell viability after C60 photoexcitation. The data obtained allow to suggest that C60-mediated photodynamic treatment is a candidate for restoration of drug-resistant leukemic cell sensitivity to induction of mitochondrial way of apoptosis.
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