Suppression of the Antioxidant System and PI3K/Akt/mTOR Signaling Pathway in Cisplatin-Resistant Cancer Cells by Quercetin.

We studied the effect of quercetin on ovarian adenocarcinoma SKOV-3 cell line and isogenic subline SKOV-3/CDDP resistant to the anticancer drug cisplatin. It was found that in resistant cells, quercetin in a concentration of 100 µM that causes a decrease in the cell viability suppressed the expression of genes encoding the key antioxidant enzymes (SOD2, CAT, GPX1, and HO-1), transcription factor Nrf2, and kinases of the PI3K/Akt/mTOR signaling pathway. In parental cells, quercetin, on the contrary, increased the expression of these genes. The results confirm the redox-dependent regulation induced by quercetin and its opposite nature in cisplatin-sensitive and cisplatin-resistant cancer cells.

Suppression of PI3K/Akt/mTOR Signaling Pathway and Antioxidant System and Reversal of Cancer Cells Resistance to Cisplatin under the Effect of Curcumin.

The effect of curcumin on the resistance of SKOV-3 human ovarian adenocarcinoma cells to cisplatin was studied. It was found that curcumin induced "reversal" of cancer cells resistance, which was associated with suppression of the expression of genes encoding the key antioxidant enzymes (SOD1, SOD2, CAT, GPX1, and HO-1) and transcription factor Nrf2 and a decrease in the expression of genes encoding kinases of the PI3K/Akt/mTOR signaling pathway. The obtained results confirm the role of redox-dependent regulation in the "reversal" of cancer cells resistance to cisplatin.

Redox-Dependent Expression of Genes Encoding NADPH Oxidase 5 and the Key Antioxidant Enzymes during Formation of Drug Resistance of Tumor Cells to Cisplatin.

Expression of genes that plays a significant role in the control of cellular redox homeostasis was studied during the development of drug resistance of human ovarian adenocarcinoma SKOV-3 cells to cisplatin. It was found that the development of drug resistance was accompanied by enhanced expression of the genes encoding the key antioxidant enzymes (SOD2, CAT, GPX1, and HO-1) and transcription factor Nrf2, as well as reduced expression of the gene encoding NOX5 isoform of NADPH oxidase. The results testify to redox-dependent development of the adaptive antioxidant response as an important process in the mechanism of formation of resistance to cisplatin.

Role of glutathione, glutathione transferase, and glutaredoxin in regulation of redox-dependent processes.

Over the last decade fundamentally new features have been revealed for the participation of glutathione and glutathione-dependent enzymes (glutathione transferase and glutaredoxin) in cell proliferation, apoptosis, protein folding, and cell signaling. Reduced glutathione (GSH) plays an important role in maintaining cellular redox status by participating in thiol-disulfide exchange, which regulates a number of cell functions including gene expression and the activity of individual enzymes and enzyme systems. Maintaining optimum GSH/GSSG ratio is essential to cell viability. Decrease in the ratio can serve as an indicator of damage to the cell redox status and of changes in redox-dependent gene regulation. Disturbance of intracellular GSH balance is observed in a number of pathologies including cancer. Consequences of inappropriate GSH/GSSG ratio include significant changes in the mechanism of cellular redox-dependent signaling controlled both nonenzymatically and enzymatically with the participation of isoforms of glutathione transferase and glutaredoxin. This review summarizes recent data on the role of glutathione, glutathione transferase, and glutaredoxin in the regulation of cellular redox-dependent processes.

Expression of peroxiredoxin 1, 2, 3, and 6 genes in cancer cells during drug resistance formation.

We studied the expression of peroxiredoxin genes (PRDX1, PRDX2, PRDX3, and PRDX6) in human erythroleukemia K652, human breast carcinoma MCF-7, and human ovarian carcinoma SKOV-3 cells during cisplatin resistance development. It was found that drug resistance formation was accompanied by a significant increase in the expression of PRDX1, PRDX2, PRDX3, PRDX6 genes in all cancer cell strains, which confirms the important contribution of redox-dependent mechanisms into the development of cisplatin resistance of cancer cells.

Expression of genes of glutathione transferase isoforms GSTP1-1, GSTA4-4, and GSTK1-1 in tumor cells during the formation of drug resistance to cisplatin.

We studied the expression of genes encoding glutathione-S-transferase isoforms GSTP1-1, GSTA4-4, and GSTK1-1 during the development of the resistance of human erythroleukemia (K562), mammary adenocarcinoma (MCF-7) and ovary adenocarcinoma (SKOV-3) cells to cisplatin (CDDP). It was found that drug resistance development in all three strains of tumor cells is associated with significant increase in hGSTP1 and hGSTA4 gene expression, whereas increased hGSTK1 gene expression was detected only in resistant K562/CDDP and MCF-7/CDDP cells.

[Current views on antioxidative activity of glutathione and glutathione-depending enzymes].

Reduced glutathione (GSH), gamma-glutamyl-L-cysteineglycine, is a tripeptide widespread in plants, animals, and man as a low-molecular weight SH-containing compound. This review presents results of published and original studies concerned with the synthesis and the role of glutathione and glutathione-dependent enzymes in antioxidative processes, such as maintenance and regulation of cell status, glutathionilation and deglutathionilation, redox-dependent signaling, and apoptosis.

[Increase in radiation resistance of an organism after administration of metabolic drug MR-33]. / Povyshenie radiorezistentnosti organizma pri deistvii metabolitnogo preparata MR-33.

Original MP-33 metabolic drug has inductive action on intracellular levels of glutathione (GSH) and GSH-related enzymes (glutathione peroxidase-GPx, glutathione S-transferase-GST) of animals and human (liver, heart, erythrocytes). Treatment of Wistar male rats with MP-33 per os (6 mg/kg) 30 min before gamma-irradiation with a dose of 7 Gy results in 35% survival and increasing of mean life. In "mother-foetus" system the induction of intracellular level of GSH, GST and GPx by MP-33 leads to enhancement of foetus radioresistance. In contrast to MP-33 us of GSH (6 and 100 mg/kg) is not effective. Perspective of MP-33 us in relation to radioecological crisis is discussed.

[Inhibitory effect of progesterone P1-1 on glutathione-s-transferase and its antiproliferative effect on human erythroleukemia K562 cells]. / Ingibiruiushchee deistvie progesterona na glutation-s-transferazy P1-1 i ego antiproliferativnyi èffekt na kletki linii K562 èritroleikemii cheloveka.

Since glutathione S-transferase P1-1 (GST P1-1) is predominantly expressed in many types of tumor cells it is regarded as its marker protein. The report discusses data on a relationship between progesterone (PS) inhibition of GST P1-1 and proliferation of human erythroleukemia K562 cells. Unlike such steroids as estrone, dexamethasone, testosterone and hydrocortisone, PS showed significant inhibitory effect (I50 = 32.5(M) and noncompetitively (Ki = 25(M) inhibited GST P1-1 isolated from human placenta. Pronounced inhibition of K562 cell proliferation by PS was in inverse correlation with the intracellular activity of GST P1-1. Also, PS injected into culture suppressed GST P1-1 expression in leukemia cells. At concentrations of 10(-8)-10(-5) M, both effects proved dose-dependent. The correlation between PS antiproliferative effect on GST P1-1 activity and expression in K562 cells is discussed in terms of its possible role played in malignant growth regulation.

[Effects of metabolic therapy on intracellular level of antioxidant system in elderly patients with ischemic heart disease]. / Effekt metabolicheskoi terapii na vnutrikletochnyi uroven' antioksidantnoi sistemy bol'nykh ishemicheskoi bolezn'iu serdtsa pozhilogo vozrasta.

Patients with ischemic heart disease (angina pectoris of functional class II and III) whose mean age was 67.4 +/- 1.67 years were divided into 3 randomized groups. 15 control patients received standard treatment. 30 and 15 patients of group 1 and 2, respectively, received standard treatment plus amino acid composition (100 mg 3 times a day sublingually) or preductal (20 mg 3 times a day)--groups 1 and 2, respectively. The treatment lasted 21 days. Before the treatment and on its day 1, 7 and 21 measurements were made of glutathione level, activity of glutathion-dependent enzymes, catalase, Cu, Zn-superoxide dismutase and malonic dialdehyde in red cells. The amino acid composition was found to raise the level of antioxidant system and suppress lipid peroxidation. Preductal raised the activity of Cu, Zn-superoxide dismutase and had an unbalanced effect on the antioxidant system.

[Oxidative stress and oxygen status in ischemic stroke].

A dynamic assessment of oxygen status of the arterial blood, activity of antioxidant system enzymes (AOS), succinatedehydrogenase (SDG), mitochondrial alpha-glycero-phosphate-dehydrogenase (alpha-GPDH) and alkaline phosphatase (AP) as well as concentrations of reduced glutathione (GSH) and secondary products of lipid peroxidation reacting with thiobarbituric acid (PLPRTA) has been carried out in patients at the acute stage of ischemic stroke of hemispheric location. Relative hyperoxia as a result of the hyperventilation syndrome was mostly pronounced on day 1 and 3. At the same time, a reduced activity of AOS system and an increase of PLPRTA concentration have been observed from the 1st day after stroke. There were also a decrease of the SDG activity and a marked (2,8 fold) increase of the alpha-GPDH activity as compared to the controls. A decrease of the AP leukocyte activity in the peripheral blood to day 7 after stroke makes possible a prognosis of good functional rehabilitation to the 21st day of the disease. Therefore, the results of the study suggest that the development of oxidative stress in patients with ischemic stroke is caused by tprimary disruption of bioenergetic processes during the reduction of AOS activity.

[[The randomized double-blind placebo-controlled study of efficacy and safety of mexidol in the complex therapy of ischemic stroke in the acute period].] / Randomizirovannoe dvojnoe slepoe placebo-kontroliruemoe issledovanie effektivnosti i bezopasnosti meksidola v kompleksnoj terapii ishemicheskogo insul'ta v ostrom periode.

The first randomized double-blind placebo-controlled study of efficacy of mexidol has been conducted. Fifty-one patients with ischemic stroke, aged 45-85 years, admitted during the first 24 hours after stroke were switched to mexidol in dosage 300 mg daily during 14 days. Twenty seven patients received the placebo using the same scheme. The significant forward dynamics in regress of neurological disturbances on the NIH scale was found to the 14th day in patients treated with mexidol as compared to the placebo group (p<0.05), along with functional rehabilitation assessed according to the dynamics of clinical scores on the Bartel scale to the 21st day after stroke (p<0.05) in patients involved in the study during the first 6 hours after disease onset. The normalization of functional brain activity was revealed in patients receiving mexidol, in comparison with the placebo, i.e. during the acute pharmacological test. A study of the antioxidant system demonstrated the increase of enzyme activity (superoxide dismutase, glutathione peroxidase, glutathione reductase) and the analysis of enzyme activity of the respiratory mitochondrial chain revealed the increase of succinate dehydrogenase activity in patients receiving mexidol. The results confirm the clinical efficacy of mexidol in the acute period of ischemic stroke in the carotid system of atherothrombotic or cardioembolic pathogenetic types, especially for its earlier (up to 6 hours) prescription, and specify mechanisms of its action (antihypoxic antihypoxic, antioxidant) in clinical conditions.