Tag Archives: cisplatin

Activation of store – operated Ca(2+) entry in cisplatin resistant leukemic cells after treatment with photoexcited fullerene C(60) and cisplatin

D. V. Franskevych, I. I. Grynyuk, S. V. Prylutska, O. P. Matyshevska

Taras Shevchenko National University of Kyiv, Ukraine;
e-mail: dashaqq@gmail.com

Ca2+-regulating system in cancer cells is suggested to be remodulated particularly by reduced store-operated Ca2+ entry (SOCE) through plasma membrane in order to maintain moderately reduced cytosolic Ca2+ concentration and to avoid apoptosis. The endoplasmic reticulum (ER) Ca2+ pool content and the size of SOCE in leukemic wild type (L1210) and resistant to cisplatin (L1210R) cells in control, after treatment with either cisplatin (1 µg/ml) or photoexcited fulleren C60 (10-5 M) alone, or their combination were estimated with the use of Indo-1 AM. The SOCE in resistant to cisplatin L1210R cells was found to be lower than in the wild-type cells. After treatment with cisplatin the decrease of thapsigargin (TG)-sensitive ER Ca2+ pool with no significant increase of SOCE was observed in L1210 cells, while no changes were detected in L1210R cells. Photoexcitation of intracellular accumulated fullerene C60 in the visible range of spectrum (410-700 nm) was accompanied by increase of SOCE not only in sensitive, but in resistant cells as well. In resistant L1210R cells treated with photoexcited C60 essential effect of cisplatin on Ca2+ homeostasis became obvious: the size of SOCE proved to be higher than after treatment with photoexcited C60 alone. The data obtained allow suggesting­ the influence of photoexcited C60 not only on Ca2+-regulating system, but on those involved in controlling cisplatin entry into drug resistant cancer cells.

Changes in oxidative stress intensity in blood of tumor-bearing rats following different modes of administration of rhenium-platinum system

K. L. Shamelashvili1, N. I. Shtemenko2, І. V. Leus3, S. O. Babiy4, O. V. Shtemenko5

 1SE “Dnipropetrovsk Medical Academy” of Health Ministry of Ukraine;
2Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
3University of Oklahoma, Oklahoma-city, USA;
4Institute of Gastroenterology, National Academy of Medical Sciences
of Ukraine, Dnipropetrovsk;
5Ukrainian State University of Chemical Technology, Dnipropetrovsk;
e-mail: shamelashvili@rambler.ru

Effects of the different modes of administration of dichlorotetra-μ-isobutyratodirhenium(ІІІ) – І – (in water solution, liposomes, nanoliposomes and together with cisplatin – in the rhenium-platinum system) on the intensity of lipid peroxidation (LP) in blood plasma and the activity of the erythrocyte antioxidant enzymes were investigated on the model of tumor growth. A decrease in the concentration of TBA-active substances caused by dirhenium compounds was shown to be independent of the administration mode and the extent of the tumor growth inhibition. I was four-times more effective in inhibition of the LP burst than any known antioxidant. I induced the increasing activity of erythrocyte superoxide dismutase and decreasing activity of catalase. In vitro experiments with native superoxide dismutase, the interaction of І with following activation of the active center of the enzyme was confirmed and the superoxide dismutase activity of І was shown, that may contribute to the enhancement of the enzyme activity in vivo. The cluster rhenium compounds may be promising nontoxic potent antioxidants capable of deactivating superoxide radicals.

Influence of antitumor system rhenium–platinum on biochemical state of the liver

V. V. Ivchuk1, T. N. Polishko1, O. A. Golichenko2,
O. V. Shtemenko2, N. I. Shtemenko1

1Oles’ Gonchar Dnepropetrovsk National University, Ukraine;
2Ukrainian State University of Chemical Technology, Dnepropetrovsk;
e-mail: n.shtemenko@i.ua

Influence of the antitumour rhenium-platinum system on biochemical liver characteristics in the model of tumor growth (Guerin carcinoma) was studied and possible hepatoprotective activi­ty of rhenium cluster compounds when introducing them in different forms was shown, that was confirmed by decreasing of diagnostic enzymes activity in blood (aminotransferase – AST 6 times and ALT 5.6 times, lactatedehydrogenase 4.9 times, γ-glutamyltranspeptidase 3.6 times) and normalization of morphological state of the liver cells. The hepatoprotective activity of the cluster rhenium compound with adamanthyl ligands was confirmed in the model of acute toxic hepatitis. Introduction of this compound led to reduction of the concentration of MDA in homogenates of liver tissue (2 times), and in blood plasma (3.8 times); to reduction of levels of diagnostic liver­ enzymes in blood – AST and ALT 5.8 and 5.5 times respectively in comparison with control group. Some aspects of the mechanism of hepatoprotection were discussed, that included the presence of conjugated systems around the quadrupol rhenium-rhenium bond and alkyl radicals with significant positive inductive effects.

Antioxidant and antitumor activity of dirhenium dicarboxylates in animals with Guerin carcinoma

I. V. Leus1, K. L. Shamelashvili1, O. D. Skorik1, S. Y. Tretyak2,
O. A. Golichenko2, O. V. Shtemenko2, N. I. Shtemenko1

1Oles Gonchar Dnipropetrovsk National University, Ukraine;
2Ukrainian State University of Chemical Technology, Dnipropetrovsk;
e-mail: ingaleus@mail.ru

The antioxidant and anticancer properties of dirhenium dicarboxylates of cis- and trans-configuration with different organic ligands in a model of tumor growth (Guerin carcinoma) were studied. It was shown that compounds of different configuration had similar antitumor effect, and dirhenium (III) cis-dicarboxylates were characterized by higher antioxidant activity and degree of activation of erythrocyte superoxide dismutase (SOD) in comparison with trans-isomers. The dependence between the structure of dirhenium (III) dicarboxylates and their ability to activate erythrocyte SOD in the model of tumor growth was shown for the first time. The in vitro studies have shown that rhenium compounds of cis- and trans-configuration interacted similarly with erythrocyte SOD, changing the protein secondary structure. In contrast to trans-dicarboxylate, for cis-dicarboxylate the SOD-like activity was demonstrated to be on the first minutes of the xantine-oxidase reaction. The studied features of the interaction between rhenium compounds and SOD in vitro explain only partly the activation of SOD in experiments in vivo. The attempt is made to explain the differences in the mechanisms of antioxidant activity of dirhenium cis- and trans-dicarboxylates.

Changes of the state of rat kidneys under Guerin carcinoma development and use of cytostatics

S. A. Babiy1, T. F. Loskutova2, N. I. Shtemenko1

1Oles Gonchar Dnipropetrovsk National University, Ukraine;
2Dnipropetrovsk State Medical Acadamy, Ukraine;
e-mail: babiy_s@meta.ua

It was shown that development of the Guerin carcinoma and introduction of cisplatin led to the damage of the kidneys of rats that was confirmed by a relative increase of weight, proteinuria, change of γ-glutamyl transpeptidase and lactate dehydrogenase activity in the urea and tissue homogenates of the kidneys, by a decrease of relative reabsorption and glomerular filtration. Introduction of nanoliposomal forms of the rhenium cluster compounds led to normalization of above mentioned diagnostic indexes and to reduction of the toxic cisplatin influence that was confirmed by biochemical and morphological investigations.

Modulation of cisplatin-induced reactive oxygen species production by fullerene C(60) in normal and transformed lymphoid cells

D. V. Franskevych, I. I. Grynyuk, S. V. Prylutska, O. P. Matyshevska

Taras Shevchenko National University of Kyiv, Ukraine;
е-mail: dashaqq@gmail.com

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.

Antioxidant properties of cluster rhenium compounds and their influence of erythropoiesis of rats with Guerin carcinoma

Y. S. Voronkova1, S. O. Babiy1, L. V. Ivans’ka2, O. V. Shtemenko3, N. I. Shtemenko1

1Oles Honchar Dnipropetrovsk National University, Ukraine;
2Municipal Institution Dnipropetrovsk Polyprofile Clinical Hospital N 4
of Dnipropetrovsk Region Council, Clinic Diagnostic Laboratory, Ukraine;
3Ukrainian State University of Chemical Technology, Dnipropetrovsk;
e-mail: yuliya_v@inbox.ru

Biochemical characteristics of kidneys, peripheral blood and bone marrow of rats in model of tumor growth under introduction of cisplatin and cis-tetrachlorodi-μ-isobutyratodirhenium(III), cis-Re2(i-C3H7COO)2Cl4 (I) have been investigated. It was shown that introduction of I alone and together with cisplatin led to decrease of biochemical markers of oxidation of lipids and proteins in tissue homogenates of the kidneys, change of enzyme activity in the urea and tissue homogenates of the kidneys, by a decrease of filtration function of kidneys. Introduction of nanoliposomal forms of the rhenium cluster compound led to a practically normal morphological picture of bone marrow and increase of the RBC (by 60%) with normalization of hematocrit counts, and decrease of quantities of destructed RBC (3.2 times) in comparison with the tumor-bearing animals. A tentative scheme of influence of cluster rhenium compound on erythropoiesis through regulation of synthesis of erythropoietin in kidneys has been proposed.