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1.
Nanoscale Res Lett ; 13(1): 81, 2018 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-29524037

RESUMEN

New representative of carbacylamidophosphates - diphenyl-N-(trichloroacetyl)-amidophosphate (HL), which contains two phenoxy substituents near the phosphoryl group, was synthesized, identified by elemental analysis and IR and NMR spectroscopy, and tested as a cytotoxic agent itself and in combination with C60 fullerene.According to molecular simulation results, C60 fullerene and HL could interact with DNA and form a rigid complex stabilized by stacking interactions of HL phenyl groups with C60 fullerene and DNA G nucleotide, as well as by interactions of HL CCl3 group by ion-π bonds with C60 molecule and by electrostatic bonds with DNA G nucleotide.With the use of MTT test, the cytotoxic activity of HL against human leukemic CCRF-CM cells with IC50 value detected at 10 µM concentration at 72 h of cells treatment was shown. Under combined action of 16 µM C60 fullerene and HL, the value of IC50 was detected at lower 5 µM HL concentration and at earlier 48 h period of incubation, besides the cytotoxic effect of HL was observed at a low 2.5 µM concentration at which HL by itself had no influence on cell viability. Binding of C60 fullerene and HL with minor DNA groove with formation of a stable complex is assumed to be one of the possible reasons of their synergistic inhibition of CCRF-CЕM cells proliferation.Application of C60 fullerene in combination with 2.5 µM HL was shown to have no harmful effect on structural stability of blood erythrocytes membrane. Thus, combined action of C60 fullerene and HL in a low concentration potentiated HL cytotoxic effect against human leukemic cells and was not followed by hemolytic effect.

2.
Nanoscale Res Lett ; 12(1): 124, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28235359

RESUMEN

Dimorfolido-N-trichloroacetylphosphorylamide (HL1) and dimorfolido-N-benzoylphosphorylamide (HL2) as representatives of carbacylamidophosphates were synthesized and identified by the methods of IR, 1H, and 31P NMR spectroscopy. In vitro HL1 and HL2 at 1 mM concentration caused cell specific and time-dependent decrease of leukemic cell viability. Compounds caused the similar gradual decrease of Jurkat cells viability at 72 h (by 35%). HL1 had earlier and more profound toxic effect as compared to HL2 regardless on leukemic cell line. Viability of Molt-16 and CCRF-CEM cells under the action of HL1 was decreased at 24 h (by 32 and 45%, respectively) with no substantial further reducing up to 72 h. Toxic effect of HL2 was detected only at 72 h of incubation of Jurkat and Molt-16 cells (cell viability was decreased by 40 and 45%, respectively).It was shown that C60 fullerene enhanced the toxic effect of HL2 on leukemic cells. Viability of Jurkat and CCRF-CEM cells at combined action of C60 fullerene and HL2 was decreased at 72 h (by 20 and 24%, respectively) in comparison with the effect of HL2 taken separately.In silico study showed that HL1 and HL2 can interact with DNA and form complexes with DNA both separately and in combination with C60 fullerene. More stable complexes are formed when DNA interacts with HL1 or C60 + HL2 structure. Strong stacking interactions can be formed between HL2 and C60 fullerene. Differences in the types of identified bonds and ways of binding can determine distinction in cytotoxic effects of studied compounds.

3.
Nanoscale Res Lett ; 12(1): 40, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28091953

RESUMEN

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.

4.
Exp Oncol ; 38(2): 89-93, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27356576

RESUMEN

AIM: To estimate the combined action of C60 fullerene and light irradiation on viability of L1210 leukemic cells, nitric oxide (NO) generation, p38 mitogen-activated protein kinase (MAPK) activity and cell cycle distribution. METHODS: Cell viability was assessed by MTT test. Light-emitting diode lamp (λ = 410-700 nm, 2.45 J/cm(2) ) was used for C60 fullerene photoexcitation. Nitrite level and NO-synthase activity were measured by Griess reaction and by conversion of L-arginine to L-citrulline, respectively. p38 MAPK activity was assessed by Western blot analysis. Cell cycle distribution was determined by flow cytometry. RESULTS: It was shown that light irradiation of C60 fullerene-treated L1210 cells was accompanied by 55% decrease of their viability at 48 h of culture. Nitrite level measured as an index of reactive NO generation was increased at the early period after C60 fullerene photoexcitation due to activation of both constitutive and inducible NO-synthase isoforms. The simultaneous activation of p38 MAPK was detected. Accumulation of L1210 cells in sub-G1 phase of cell cycle was observed after C60 fullerene photoexcitation. CONCLUSION: Photoexcited C60 fullerene exerts cytotoxic effect, at least in part, through triggering production of reactive NO species and activation of p38 kinase apoptotic pathways in L1210 leukemic cells.


Asunto(s)
Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Fulerenos/farmacología , Leucemia/tratamiento farmacológico , Óxido Nítrico/metabolismo , Fármacos Fotosensibilizantes/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Ciclo Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Leucemia/metabolismo , Ratones , Óxido Nítrico Sintasa de Tipo II/metabolismo , Rayos Ultravioleta
5.
Ukr Biochem J ; 88(1): 44-50, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-29227077

RESUMEN

The early response of normal (Wistar rat thymocytes) and transformed (mice lymphoid leukemia L1210) cells to treatment with anticancer drug cisplatin or to combined treatment with cisplatin and carbon nanostructure fullerene C60 was studied. We demonstrated with fluorescent probes DCFH-DA and TMRE that cisplatin at concentration 1 µg/ml induced reactive oxygen species (ROS) production and decreased the value of mitochondrial membrane potential in both cell types. The combined treatment with cisplatin (1 µg/ml) and fullerene C60 (7.2 µg/ml) was shown to be followed by oppositely directed modulation of ROS production in thymocytes and L1210 cells. Cisplatin-induced ROS production was intensified in L1210 cells, while in thymocytes it was decreased. It is supposed that the different effects of combined treatment are associated with peculiarities of fullerene C60 accumulation and localization in normal and cancer cells.


Asunto(s)
Antineoplásicos/farmacología , Cisplatino/farmacología , Fulerenos/farmacología , Linfocitos/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Timocitos/efectos de los fármacos , Animales , Línea Celular Tumoral , Combinación de Medicamentos , Interacciones Farmacológicas , Fluoresceínas/química , Colorantes Fluorescentes/química , Linfocitos/metabolismo , Linfocitos/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Especificidad de Órganos , Compuestos Organometálicos/química , Cultivo Primario de Células , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/agonistas , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Timocitos/citología , Timocitos/metabolismo
6.
Exp Oncol ; 37(3): 187-91, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26422102

RESUMEN

AIM: To evaluate the viability of leukemic cells sensitive (L1210S) and resistant (L1210R) to cisplatin, ROS production and free cytosolic Ca(2+) concentration under treatment with cisplatin or its combination with photoexcited fullerene C60. METHODS: Cell viability was assessed by the MTT reduction assay. Light-emitting diode lamp (2.45 J/cm(2)) was used for photoexcitation of intracellular accumulated fullerene C60. Free cytosolic calcium concentration ([Ca(2+)]i) and ROS production in cells were estimated with the use of fluorescent probes Indo-1 and 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA), respectively. RESULTS: It is shown that viability of L1210R cells wasn't changed under treatment with cisplatin in concentration range 0.1-10 µg/ml. 50% and 30% decrease of L1210S cells were observed after 24 h of incubation with cisplatin at concentrations 5 and 1 µg/ml, respectively. Intensification of extranuclear cytotoxic effects (ROS production and [Ca(2+)]i increase) after treatment with 1 µg/ml was detected in L1210S, but not in L1210R cells. The most strongly pronounced increase of ROS production and [Ca(2+)]i in both L1210 cell lines was revealed in dynamics after combined treatment with cisplatin (1 µg/ml) and photoexcited fullerene C60 (10(-5) M) and was followed by decreased viability of not only L1210S, but of L1210R cells as well.. CONCLUSION: Combined treatment with photoexcited C60 and cisplatin allowed to decrease effective concentration of cisplatin against parental L1210 cells and to increase sensibility of resistant cells to the drug.


Asunto(s)
Cisplatino/administración & dosificación , Cisplatino/toxicidad , Resistencia a Antineoplásicos , Fulerenos , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fulerenos/química , Humanos , Leucemia/metabolismo , Ratones , Especies Reactivas de Oxígeno/metabolismo
7.
Ukr Biochem J ; 87(6): 154-61, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-27025070

RESUMEN

Structural analogues of ß-diketones--dimethyl-N-(benzoyl)amidophosphate (HCP) and dimethyl-N-(phenylsulfonyl)amidophosphate (HSP) were synthesized and identified by the methods of IR, 1H and 31P NMR spectroscopy. Screening of biological activity and calculation of physicochemical parameters of HCP and HSP compounds were done with the use of PASS and ACD/Labs computer programs. A wide range of biological activity of synthesized compounds, antitumor activity in particular, has been found. Calculations of the bioavailability criteria indicate that the investigated compounds have no deviations from Lipinski's rules. HCP compound is characterized by a high lipophilicity at physiological pH as compared to HSP. It was found that cytotoxic effect of the studied compounds on the leukemic L1210 cells was of time- and dose-dependent character. HCP is characterized by more pronounced and early cytotoxic effects as compared to HSP. It was shown that 2.5 mM HCP increased ROS production 3 times in the early period of incubation, and decreased cell viability by 40% after 48 h, and by 66%--after 72 h. Based on the computer calculation and undertaken research, HCP was selected for target chemical modifications and enhancement of its antitumor effect.


Asunto(s)
Antineoplásicos/farmacología , Citotoxinas/farmacología , Cetonas/farmacología , Modelos Químicos , Organofosfatos/farmacología , Especies Reactivas de Oxígeno/agonistas , Animales , Antineoplásicos/síntesis química , Linfocitos B/efectos de los fármacos , Linfocitos B/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Simulación por Computador , Citotoxinas/síntesis química , Relación Dosis-Respuesta a Droga , Interacciones Hidrofóbicas e Hidrofílicas , Cetonas/síntesis química , Ratones , Organofosfatos/síntesis química , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad
8.
Ukr Biokhim Zh (1999) ; 84(6): 58-63, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23387269

RESUMEN

The values of endoplasmic reticulum Ca(2+)-pool and store-operated Ca2+ entry (SOCE) were estimated in rat thymocytes and Jurkat cells loaded with indo-1 and treated with thapsigargin. It was shown that the relative value of SOCE in thymocytes was substantially lower than in Jurkat cells. Significant increase of SOCE in Jurkat cells preincubated with 10(-5) M C60 and exposed to uv/visible light irradiation was detected at 1-3 h after exposure. At this time FCCP-induced Ca(2+)-release from mitochondria was shown to be reduced, while cytochrome c level into the cytoplasm of Jurkat cells, detected by Western blot analysis, to be increased. It is supposed that Ca2+ flux remodulation induced by photoexcited fullerene C60 in Jurkat cells might be involved in the initiation of signalling events leading to cell apoptosis.


Asunto(s)
Canales de Calcio/metabolismo , Calcio/metabolismo , Citocromos c/metabolismo , Fulerenos/farmacología , Mitocondrias/efectos de los fármacos , Fármacos Fotosensibilizantes/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Carbonil Cianuro p-Trifluorometoxifenil Hidrazona/farmacología , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/efectos de la radiación , Inhibidores Enzimáticos/farmacología , Colorantes Fluorescentes , Humanos , Indoles , Células Jurkat , Luz , Mitocondrias/metabolismo , Mitocondrias/efectos de la radiación , Especificidad de Órganos , Ionóforos de Protónes/farmacología , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Tapsigargina/farmacología , Timocitos/citología , Timocitos/efectos de los fármacos , Timocitos/metabolismo , Timocitos/efectos de la radiación
9.
Cancer Nanotechnol ; 2(1-6): 105-110, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-26069489

RESUMEN

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.

10.
Exp Oncol ; 32(1): 29-32, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20332760

RESUMEN

AIM: To estimate the viability of normal and transformed T-lymphocytes after UV/Vis irradiation in the presence of pristine fullerenes C(60). METHODS: Thymocytes were isolated from Wistar rats' thymus. Murine leukemia L1210 and human lymphoma Jurkat cells were used in this study. Mercury-vapor lamp was used for fullerenes C(60) photoexcitation. Cytotoxicity was etermined by MTT assay. Changes in cell morphology were monitored by phase-contrast light microscopy. RESULTS: fullerenes C(60) exhibit cytotoxic effect against transformed T-lymphocytes when combined with UV/Vis irradiation (320-600 nm). Photoinduced effect was enhanced with the increasing of irradiation time period and C(60) concentration, cell death was registered after 24 hours incubation. Fullerenes C(60) photocytotoxicity against normal T-lymphocytes (thymocytes) was not observed. CONCLUSION: The present study suggests that pristine fullerenes C(60) have the potential to be an effective photosensitizer and exhibit cytotoxic effect on transformed T-cells in vitro .


Asunto(s)
Fulerenos/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/efectos de la radiación , Rayos Ultravioleta , Animales , Línea Celular Transformada , Humanos , Células Jurkat , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Fotoquímica , Ratas , Ratas Wistar , Linfocitos T/patología , Células Tumorales Cultivadas
11.
Ukr Biokhim Zh (1999) ; 82(4): 121-7, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21513214

RESUMEN

The viability of normal (Wistar rat thymocytes) and transformed (human leukemia Jurkat cells) T cells after UV/Vis irradiation in the presence of pristine C60 fullerene was studied. The data obtained have shown that C60 fullerene exhibits cytotoxic effect against transformed T lymphocytes when combined with UV/Vis irradiation using mercury-vapor lamp (320-600 nm). C60 fullerene photocytotoxicity was not detected in thymocytes. C60-dependent photoinduced apoptosis of Jurkat cells was confirmed by DNA fragmentation and caspase-3 activation. No substantial increase of caspase-3 activation was observed in thymocytes treated with C60 fullerene plus irradiation, while antileukemic agent cytosine arabinoside was shown to induce caspase-3 activation both in Jurkat cells and thymocytes. The data obtained may be useful for development of photosensitizers for photodynamic therapy with selective action on leukemia cells.


Asunto(s)
Apoptosis , Fulerenos/farmacología , Luz , Fármacos Fotosensibilizantes/farmacología , Linfocitos T , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Western Blotting , Caspasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Fragmentación del ADN/efectos de los fármacos , Fragmentación del ADN/efectos de la radiación , Femenino , Humanos , Células Jurkat , Fotoquimioterapia , Ratas , Ratas Wistar , Linfocitos T/efectos de los fármacos , Linfocitos T/patología , Linfocitos T/efectos de la radiación , Timo/citología , Timo/efectos de los fármacos , Timo/efectos de la radiación , Factores de Tiempo
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