Tag Archives: doxorubicin

Antitoxic and antioxidant effects of N-stearoylethanolamin in the content of nanocomposite complex with doxorubicin in organs of mice with Lewis carcinoma

E. A. Gudz1, N. M. Hula1, T. N. Goridko1, Y. M. Bashta1,
A. I. Voyeikov1, A. G. Berdyshev1, H. V. Kosiakova2,
R. R. Panchuk3, R. S. Stoika2, A. A. Ryabtseva3, O. S. Zaichenko3

1Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
e-mail: ngula@biochem.kiev.ua;
2Institute Biology of Cell, National Academy of Sciences of Ukraine, Lviv;
3National University “Lvov Politekhnika”, Ukraine

The aim of the study was to evaluate the possibility to reduce the doxorubicin toxic effects by its immobilization with N-stearoylethanolamine (NSE) on nanocarier polyethylene glycol. The studied  parameters of the doxorubicin toxicity were: the level of creatinine in the mice blood plasma and activity of alanine aminotransferase and aspartate aminotransferase in the blood plasma of mice. The activity of catalase superoxide dismutase, glutathione peroxidase and intensity of lipid peroxidation was determined in the tissues of the heart, kidneys and liver. Doxorubicin in the content of nanocarrier alone caused an increase of serum creatinine and aspartateaminotrasferase activity in plasma of experimental animals with carcinoma. Nanocomposite which contained doxorubicin and NSE, did not cause an increase of these parameters. It has been shown that the administration of a carrier containing doxorubicin to mice with Lewis lung carcinoma caused the decrease of  catalase  activity in mice with carcinoma. The combination of NSE and doxorubicin on the carrier led to the normalization of this parameter to the level of intact animals. NSE immobilized on a carrier together with doxorubicin caused a decrease in the activity of superoxide dismutase in the kidney tissue of mice with tumor. The tumor growth caused the increase of the of superoxide dismutase in mice. The administration of a carrier which contained doxorubicin and NSE normalized superoxide dismutase in heart tissue contrary of kidney. The obtained results show the antitoxic and antioxidant effects of N-stearoylethanolamine immobilized in the nanocarrier complex together with doxorubicin.

Organ-specific antitoxic effects of N-stearoilethanolamine male mice with lewis carcinoma under indoxorubicin intoxication

E. A. Goudz, N. M. Gulа, T. N. Goridko, Y. N. Bashta, A. I. Voyeikov

Palladin Institute of Biochemistry,
National Academy of Sciences of Ukraine, Kyiv;
e-mail: ngula@biochem.kiev.ua

With the introduction of doxorubicin into mice with Lewis carcinoma in the heart and liver tissues and kidney the organ-antitoxic effects of N-stearoilethanolamine (NSE) were found, which depended on its concentration. Administration of doxorubicin to male mice leads to an increase in the level of urea and creatinine, as well as activation of ALT in blood plasma. Introduction of NSE resulted in normalization of these parameters to the level of intact animals. In the heart tissue  doxorubicin has multi-directional effects on the activity of antioxidant enzymes, in particular it decreases the activity of catalase and superoxide dismutase activity increases. Introduction of NSE normalizes these two indicators. It was found that tumor growth leads to an increase in the activity of glutathione peroxidase and superoxide dismutase. Introduction of NSE normalizes activity of these enzymes. Doxorubicin causes an increase in catalase activity in the kidney of mice with tumour, NSE prevented the increase in the activity of the above enzyme. The cancer process leads to increased levels of catalase activity in the liver of tumour-bearing mice, the introduction of NSE decreases the enzyme activity.

Action of free and polymer carrier encapsulated doxorubicin towards HCT116 cells of human colorectal carcinoma

Yu. V. Senkiv1,2,4, P. Heffeter2, A. O. Riabtseva3, N. M. Boiko1,
O. S. Zaichenko3, N. Ye. Mitina3, W. Berger2, R. S. Stoika1

1Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv;
2Institute for Cancer Research, Medical University of Vienna, Austria;
3National University Lviv Polytechnic, Ukraine;
4Ivan Franko Lviv National University, Ukraine;
e-mail: stoika@cellbiol.lviv.ua

Development of novel nanoscale functionali­zed carriers is nowadays one of the most urgent problems in cancer treatment.  The aim of our study was to compare the antineoplastic effect of free doxorubicin and its complex with a nanoscale polymeric carrier towards HTC116 colorectal carcinoma cells. It was established that application of the complex of poly(5-tret-butylperoxy)-5-methyl-1-hexene-3-in-co-glycydyl metacrylat)-graft-polyethyleneglycol (poly(VEP-GMA-PEG)-graft-PEG), where VEP  – 5-tret-butylperoxy)-5-methyl-1-hexene-3-in; GMA – glycydyl metacrylat; graft-PEG – graft-polyethyleneglycol accordingly, functionali­zed with phosphatidylcholine for doxorubicin delivery increased 10 times the efficiency of cytotoxic action of this drug, as compared wich such efficiency in case of the action of free doxorubicin. The encapsulated form of doxorubicin caused more intensive cleavage of the reparation enzyme PARP and longer delay in G2/M cell cycle arrest, compared to such effects of free doxorubicin. The developed carrier itself is non-toxic to the used mammalian cells and does not cause impairment in their cell cycle. A deletion in both alleles of p53 gene did not affect the antineoplastic action of doxorubicin that was immobilized on the nanoscale carrier. Thus, p53-dependent signaling pathways are not involved in the cytotoxic action of doxorubicin-carrier complex. It is suggested that novel nanoscale polymeric carrier poly(VEP-GMA-PEG)-graft-PEG functionalized with phosphatidylcholine could be a promising carrier for targeted delivery of anticancer drugs.

Biochemical indicators of hepatotoxicity in blood serum of rats under the effect of novel 4-thiazolidinone derivatives and doxorubicin and their complexes with polyethyleneglycol-containing nanoscale polymeric carrier

L. I. Kоbylinska1, D. Ya. Havrylyuk1, А. О. Ryabtseva2, N. E. Mitina2,
О. S. Zаichenko2, R. B. Lesyk1, B. S. Zіmenkovsky1, R. S. Stoika3

1Danylo Halytsky Lviv National Medical University, Ukraine;
e-mail: lesya8@gmail.com;
2Lviv Polytechnic National University, Ukraine;
3Іnstitute of Cell Biology, National Academy of Sciences of Ukraine, Lviv

The aim of this study was to compare the effect of new synthetic 4-tiazolidinone derivatives (compounds 3882, 3288 and 3833) and doxorubicin (positive control) in free form and in their complexes with synthetic polyethyleneglycol-containing nanoscale polymeric carrier on the biochemical indicators of hepatotoxicity in blood serum of rats. The activity of enzymes considered as the markers of hepatotoxicity, as well as the concentration of total protein, urea and creatinine were measured in blood serum of rats. It was found that after injection of investigated compounds the activities of alanine aminotransferase, alkaline phosphatase and α-amylase increased in comparison to control. Doxorubicin injection was accompanied by 4-fold increase in the activity of γ-glutamyltransferase, and injection of compound 3833 led to 2.5-fold elevation of the activity of this enzyme. Complexation of these аntineoplastic derivatives with a synthetic nanocarrier lowered the activity of the investigated enzymes substantially if compared to the effect of these compounds in free form. The most evident decrease was measured for α-amylase, γ-glutamyltransferase and lactate dehydrogenase activities. The normalization of concentrations of total protein, urea and creatinine in blood serum of rats treated with complexes of the studied compounds with a polymeric carrier comparing with their introduction in free form was also detected. Thus, the immobilization by novel polymeric carrier of anticancer drugs possessing high general toxicity in the treated organism mitigates their toxic effect, which is evident as normalization of specific biochemical indicators of the hepatodestructive effects of the anticancer drugs.

Metalloproteins during development of Walker-256 carcinosarcoma resistant phenotype

V. F. Chekhun, Yu. V. Lozovska, A. P. Burlaka, I. I. Ganusevich,
Yu. V. Shvets, N. Yu. Lukianova, I. M. Todor, D. V. Demash,
A. A. Pavlova, L. A. Naleskina

R. E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology,
National Academy of Sciences of Ukraine, Kyiv;
e-mial: Lozovskaya.2012@mail.ru

The study was focused on the detection of changes in serum and tumor metal-containing proteins in animals during development of doxorubicin-resistant phenotype in malignant cells after 12 courses of chemotherapy. We found that on every stage of resistance development there was a significant increase in content of ferritin and transferrin proteins (which take part in iron traffick and storage) in Walker-256 carcinosarcoma tissue. We observed decreased serum ferritin levels at the beginning stage of the resistance development and significant elevation of this protein levels in the cases with fully developed resistance phenotype. Transferrin content showed changes opposite to that of ferritin. During the development of resistance phenotype the tumor tissue also exhibited increased ‘free iron’ concentration that putatively correlate with elevation of ROS generation and levels of MMP-2 and MMP-9 active forms. The tumor non-protein  thiol content increases gradually as well. The serum of animals with early stages of resistance phenotype development showed high ceruloplasmin activity and its significant reduction after loss of tumor sensitivity to doxorubicin. Therefore, the development of resistance phenotype in Walker-256 carcinosarcoma is accompanied by both the deregulation of metal-containing proteins in serum and tumor tissue and by the changes in activity of antioxidant defense system. Thus, the results of this study allow us to determine the spectrum of metal-containing proteins that are involved in the development of resistant tumor phenotype and that may be targeted for methods for doxorubicin sensitivity correction therapy.

C(60) fullerene prevents genotoxic effects of doxorubicin in human lymphocytes in vitro

K. S. Afanasieva1, S. V. Prylutska1, A. V. Lozovik1, K. I. Bogutska1, A. V. Sivolob1,
Yu. I. Prylutskyy1, U. Ritter2, P. Scharff2

1Taras Shevchenko National University of Kyiv, Ukraine;
е-mail: prylut@ukr.net;
2Technical University of Ilmenau, Institute of Chemistry
and Biotechnology, Ilmenau, Germany 

The self-ordering of C60  fullerene, doxorubicin and their mixture precipitated from aqueous solutions was investigated using atomic-force microscopy. The results suggest the complexation between the two compounds. The genotoxicity of doxorubicin in complex with C60  fullerene (С60+Dox) was evaluated in vitro with comet assay using human lymphocytes. The obtained results show that the C60  fullerene prevents the toxic effect of Dox in normal cells and, thus, С60+Dox complex might be proposed for biomedical application.