Renocardiac syndrome type 4 (RCS4) is a common comorbid pathology, but the mechanisms of kidney dysfunction-induced cardiac remodeling and the involvement of cardiac progenitor cells (CPCs) in this process remain unclear. The aim of this study was to investigate the structural and functional changes in the cardiac muscle in RCS4 induced by unilateral ureteral obstruction (UUO) and the role of nestin+ CPCs in these. Heart function and localization of nestin+ cells in the myocardium were assessed using nestin-GFP transgenic mice subjected to UUO for 14 and 28 days. UUO resulted in cardiac hypertrophy, accompanied by an elongation of the QRS wave on the ECG, decreased expression of Cxcl1, Cxcl9, and Il1b, reduced the number of CD11b+ cells, and increased in titin isoform parameters, such as T1/MHC and TT/MHC ratios, without changes in fibrosis markers. The number of nestin+ cells increased in the myocardium with increased duration of UUO and displayed an SCA-1+TBX5+ phenotype, consistent with CPCs. Thus, cardiac pathology in RCS4 was manifested by cardiomyocyte hypertrophy with changes in the electrophysiological phenotype of the heart, not accompanied by fibrosis or inflammation. Nestin+ cardiac cells retained the CPC phenotype during UUO, and their number increased, which suggests their participation in regenerative processes in the heart.

Obstructive nephropathy is a common clinical condition caused by urinary retention. After urine flow is restored, kidney function is recovered. However, the effectiveness of this process can be influenced by many factors, including the age of the patient. In this study, we analyzed the following parameters in young and old rats subjected to a 3-day reversible unilateral ureteral obstruction (R-UUO): AKI severity, renal tissue proliferation and histology, inflammatory and fibrosis marker expression, as well as autophagosomal-lysosomal and mitochondrial function. Compared to old rats, young animals exhibited more pronounced renal tissue proliferation and higher expression of profibrotic markers (Col1a1, Fn1, Tgfb1, MMP2), but diminished expression of pro-inflammatory markers (Il1b, Tnfa, Cd32) in response to R-UUO. Additionally, young rats showed more pronounced activity of autophagy, as indicated by increased beclin-1 levels. R-UUO induced severe damage to the mitochondrial respiratory chain in old animals, as indicated by reduced complex I, IV, cytochrome c, VDAC protein levels, and impaired mitochondrial biogenesis (associated with decreased Pgc1a mRNA expression). Thus, we demonstrated that despite restored urine outflow, kidneys exhibited autophagy activation, inflammatory response, and mitochondrial dysfunction after R-UUO. Negative alterations in the kidney were age-dependent indicating necessity for therapeutic strategies optimization for patients of different ages.

The aim of this work was to test whether we can treat cholestasis with dietary approaches applied after the onset of the disease. The effects of intermittent fasting and dietary restriction on liver damage caused by common bile duct ligation (BDL) in rats were studied, with particular attention paid to changes in the activity of enzymes of energy metabolism and antioxidant protection. Morphological changes in liver tissue and serum markers of liver damage were assessed in rats with BDL kept for one month on ad libitum diet, intermittent fasting, or 35% dietary restriction. We studied parameters of glucose metabolism (activity of glycolysis and gluconeogenesis enzymes), TCA cycle, and indicators of oxidative stress and redox status of the liver tissue. Dietary restriction resulted in an increase in gluconeogenesis activity, antioxidant capacity, and autophagy activation. When implemented after BDL, none of the dietary restriction protocols reduced the level of oxidative stress, detrimental morphological and biochemical alterations, or the fibrosis progression. Thus, under severe damage and oxidative stress developing in cholestasis, dietary restrictions are not hepatoprotective and can only be used in a pre-treatment mode.

One of the therapeutic approaches to age-related diseases is modulation of body cell metabolism through certain diets or their pharmacological mimetics. The ketogenic diet significantly affects cell energy metabolism and functioning of mitochondria, which has been actively studied in various age-related pathologies. Here, we investigated the effect of the ketogenic diet mimetic beta-hydroxybutyrate (BHB) on the expression of genes regulating mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam), quality control (Sqstm1), functioning of the antioxidant system (Nfe2l2, Gpx1, Gpx3, Srxn1, Txnrd2, Slc6a9, Slc7a11), and inflammatory response (Il1b, Tnf, Ptgs2, Gfap) in the brain, lungs, heart, liver, kidneys, and muscles of young and old rats. We also analyzed mitochondrial DNA (mtDNA) copy number, accumulation of mtDNA damage, and levels of oxidative stress based on the concentration of reduced glutathione and thiobarbituric acid-reactive substances (TBARS). In some organs, aging disrupted mitochondrial biogenesis and functioning of cell antioxidant system, which was accompanied by the increased oxidative stress and inflammation. Administration of BHB for 2 weeks had different effects on the organs of young and old rats. In particular, BHB upregulated expression of genes coding for proteins associated with the mitochondrial biogenesis and antioxidant system, especially in the liver and muscles of young (but not old) rats. At the same time, BHB contributed to the reduction of TBARS in the kidneys of old rats. Therefore, our study has shown that administration of ketone bodies significantly affected gene expression in organs, especially in young rats, by promoting mitochondrial biogenesis, improving the functioning of the antioxidant defense system, and partially reducing the level of oxidative stress. However, these changes were much less pronounced in old animals.

There is an increasing accumulation of data on the exceptional importance of mitochondria in the occurrence and treatment of cancer, and in all lines of evidence for such participation, there are both energetic and non-bioenergetic functional features of mitochondria. This analytical review examines three specific features of adaptive mitochondrial changes in several malignant tumors. The first feature is characteristic of solid tumors, whose cells are forced to rebuild their energetics due to the absence of oxygen, namely, to activate the fumarate reductase pathway instead of the traditional succinate oxidase pathway that exists in aerobic conditions. For such a restructuring, the presence of a low-potential quinone is necessary, which cannot ensure the conventional conversion of succinate into fumarate but rather enables the reverse reaction, that is, the conversion of fumarate into succinate. In this scenario, complex I becomes the only generator of energy in mitochondria. The second feature is the increased proliferation in aggressive tumors of the so-called mitochondrial (peripheral) benzodiazepine receptor, also called translocator protein (TSPO) residing in the outer mitochondrial membrane, the function of which in oncogenic transformation stays mysterious. The third feature of tumor cells is the enhanced retention of certain molecules, in particular mitochondrially directed cations similar to rhodamine 123, which allows for the selective accumulation of anticancer drugs in mitochondria. These three features of mitochondria can be targets for the development of an anti-cancer strategy.

Worldwide, interest in mitochondria is constantly growing, as evidenced by scientific statistics, and studies of the functioning of these organelles are becoming more prevalent than studies of other cellular structures. In this analytical review, mitochondria are conditionally placed in a certain cellular center, which is responsible for both energy production and other non-energetic functions, without which the existence of not only the eukaryotic cell itself, but also the entire organism is impossible. Taking into account the high multifunctionality of mitochondria, such a fundamentally new scheme of cell functioning organization, including mitochondrial management of processes that determine cell survival and death, may be justified. Considering that this issue is dedicated to the memory of V. P. Skulachev, who can be called mitocentric, due to the history of his scientific activity almost entirely aimed at studying mitochondria, this work examines those aspects of mitochondrial functioning that were directly or indirectly the focus of attention of this outstanding scientist. We list all possible known mitochondrial functions, including membrane potential generation, synthesis of Fe–S clusters, steroid hormones, heme, fatty acids, and CO2. Special attention is paid to the participation of mitochondria in the formation and transport of water, as a powerful biochemical cellular and mitochondrial regulator. The history of research on reactive oxygen species that generate mitochondria is subject to significant analysis. In the section “Mitochondria in the Center of Death”, special emphasis is placed on the analysis of what role and how mitochondria can play and determine the program of death of an organism (phenoptosis) and the contribution made to these studies by V. P. Skulachev.

The development of liver fibrosis is one of the most severe and life-threatening outcomes of chronic liver disease (CLD). For targeted therapy of CLD, it is highly needed to reveal molecular targets for normalizing metabolic processes impaired in damaged liver and associated with fibrosis. In this study, we investigated the morphological and biochemical changes in rat liver models of fibrosis induced by chronic administration of thioacetamide, carbon tetrachloride, bile duct ligation (BDL), and ischemia/reperfusion (I/R), with a specific focus on carbohydrate and energy metabolism. Changes in the levels of substrates and products, as well as enzyme activities of the major glucose metabolic pathways (glycolysis, glucuronidation, and pentose phosphate pathway) were examined in rat liver tissue after injury. We examined key markers of oxidative energy metabolism, such as the activity of the Krebs cycle enzymes, and assessed mitochondrial respiratory activity. In addition, pro- and anti-oxidative status was assessed in fibrotic liver tissue. We found that 6 weeks of exposure to thioacetamide, carbon tetrachloride, BDL or I/R resulted in a decrease in the activity of glycolytic enzymes, retardation of mitochondrial respiration, elevation of glucuronidation, and activation of pentose phosphate pathways, accompanied by a decrease in antioxidant activity and the onset of oxidative stress in rat liver. Resemblance and differences in the changes in the fibrosis models used are described, including energy metabolism alterations and antioxidant status in the used fibrosis models. The least pronounced changes in glucose metabolism and mitochondrial functions in the I/R and thioacetamide models were associated with the least advanced fibrosis. Ultimately, liver fibrosis significantly altered the metabolic profile in liver tissue and the flux of glucose metabolic pathways, which could be the basis for targeted therapy of liver fibrosis in CLD caused by toxic, cholestatic, or I/R liver injury.

Alzheimer's-like disease was simulated in female adult Wistar CRL(WI) WUBR rats by 6-week intragastric administration of aluminum chloride at a dose of 200 mg/kg body mass. In the presence of the developed oxidative stress (OS), we found a decrease in the activities of the tricarboxylic acid cycle (TCA cycle) enzymes and an increase in the activities of the pentose phosphate pathway (PPP) dehydrogenases, as well as a reduction of SH-and SS-groups in proteins along with an increased SH/SS ratio and glutathionylation with simultaneous decreases of glutathione (GSH) and the GSH/GSSG ratio and its redox potential. The glutathione system enzymes were changed multidirectionally, with glutathione reductase remaining stable. Decreased activities of GSH biosynthesis enzymes and cysteine content were noticed. The intragastric administration of the CoA biosynthesis modulators D-panthenol (PL), D-pantethine, or D-homopantothenate (HPA) at a dose of 200 mg/kg from the fifth week of the experiment caused either reduction or leveling of OS manifestations in blood plasma, an increase in acetyl cholinesterase, normalization of the activities of TCA cycle and PPP enzymes and the P-SH level (not the SH/SS ratio), and a significant reduction of S-glutathionylation, as well as increases in the GSH level, the GSH/GSSG ratio and the redox potential in the hemispheres. The effect of CoA system modulators was manifested in activation of glutathione transferase, a decrease of glutathione peroxidase and less evident activation of GSH biosynthesis enzymes (that is, PL) although they contributed to the elevation of the cysteine content due to reduced protein S-cysteinylation. The levels and the ratio of CoA/acetyl-CoA (except for PL) were not changed by toxicosis and the OS modulators. The feasibility of nonconenzyme effects was confirmed by the administration of HPA. The phenomenon of redox activity of the CoA biosynthesis modulators with clearly directional effects on the glutathione system and the TCA cycle and PPP enzymes during alleviation of OS and aluminum neurotoxicosis is discussed.

Mitochondria in a cell can unite and organize complex, extended structures that occupy the entire cellular volume, providing an equal supply with energy in the form of ATP synthesized in mitochondria. In accordance with the chemiosmotic concept, the oxidation energy of respiratory substrates is largely stored in the form of an electrical potential difference on the inner membrane of mitochondria. The theory of the functioning of extended mitochondrial structures as intracellular electrical wires suggests that mitochondria provide the fastest delivery of electrical energy through the cellular volume, followed by the use of this energy for the synthesis of ATP, thereby accelerating the process of ATP delivery compared to the rather slow diffusion of ATP in the cell. This analytical review gives the history of the cable theory, lists unsolved critical problems, describes the restructuring of the mitochondrial network and the role of oxidative stress in this process. In addition to the already proven functioning of extended mitochondrial structures as electrical cables, a number of additional functions are proposed, in particular, the hypothesis is put forth that mitochondrial networks maintain the redox potential in the cellular volume, which may vary depending on the physiological state, as a result of changes in the three-dimensional organization of the mitochondrial network (fragmentation/fission–fusion). A number of pathologies accompanied by a violation of the redox status and the participation of mitochondria in them are considered.

Alzheimer’s-like disease was simulated in female adult Wistar CRL(WI) WUBR rats by 6-week intragastric administration of aluminium chloride at a dose of 200 mg/kg body mass. In the presence of developed oxidative stress (OS), we found a decrease in the activities of tricarboxylic acid cycle (TCA cycle) enzymes and an increase in the activities of pentose phosphate pathway (PPP) dehydrogenases as well as a reduction of SH-and SS-groups in proteins (P) along with the increased SH/SS ratio and glutathionylation with simultaneous decreases of glutathione (GSH) and the GSH/GSSG ratio and its redox potential in the brain hemispheres. The glutathione system enzymes were changed multidirectionally, with glutathione reductase remaining stable. Decreased activities of GSH biosynthesis enzymes and cysteine content were noticed. The intragastric administration of the CoA biosynthesis modulators D-panthenol (PL), D-pantethine or D-homopantothenate (HPA) at a dose of 200 mg/kg since the 5th week of the experiment caused either reduction or leveling of OS manifestations in blood plasma, an increase in acetyl cholinesterase, normalization of the activities of TCA cycle and PPP enzymes, P-SH level (not the SH/SS ratio) and a considerable reduction of S-glutathionylation as well as increases in GSH level, the GSH/GSSG ratio and redox potential in the hemispheres. The effect of CoA system modulators was manifested in activation of glutathione transferase, a decrease of glutathione peroxidase and less evident activation of GSH biosynthesis enzymes (PL) although they contributed to the elevation of cysteine content due to the reduced protein S-cysteinylation. The levels and the ratio of CoA/acetyl-CoA (except for PL) were not changed by toxicosis and the OS modulators. The feasibility of non-conenzyme effects was confirmed by the administration of HPA. The phenomenon of redox activity of the CoA biosynthesis modulators with clearly directional effects on the glutathione system and the TCA cycle and PPP enzymes during alleviation of OS and aluminium neurotoxicosis is discussed.

An Alzheimer-like pathological process was induced in mature female Wistar CRL: (WI) WUBR rats using aluminum chloride (200 mg/kg, intragastrically, 6 weeks) in order to model redox imbalance and oxidative stress (OS) in the hippocampus and study the possibilities of their correction 2 weekly administration of coenzyme A biosynthesis modulators (panthenol – PL, pantethine – PT, homopantothenate – HP) at a dose of 200 mg/kg intragastrically for 2 weeks). Against the background of activation of peroxidation processes and a decrease in acetylcholinesterase activity, a decrease in the reduction potential of glutathione and the level of the acid-soluble fraction of CoA was observed with a simultaneous increase in the activity of glutathione-metabolizing enzymes (GR, GPx, GST), the process of S-glutathionylation of proteins and the level of protein thiols. The consumption of the precursors of CoA biosynthesis in full (PL, PT) or in part (HP) had an antioxidant effect, restored the activity of AChE, the level and reduction potential of glutathione and glutathione-metabolizing enzymes, the process of S-glutathionylation, and stimulated the activity of enzymes generating NADPH+. Taking into account the low modulating effect of coenzyme precursors on the level of CoA in the hippocampus and their high redox pharmacological activity, their non-coenzymatic effect on redox mechanisms leading to an increase in the bioavailability of reducing equivalents and energy status is assumed.

Age‐related impairment of coordination of the processes of maintaining mitochondrial homeostasis is associated with a decrease in the functionality of cells and leads to degenerative processes. mtDNA can be a marker of oxidative stress and tissue degeneration. However, the mechanism of accumulation of age‐related damage in mtDNA remains unclear. In the present study, we analyzed the accumulation of mtDNA damage in several organs of rats during aging and the possibility of reversing these alterations by dietary restriction (DR). We showed that mtDNA of brain compartments (with the exception of the cerebellum), along with kidney mtDNA, was the most susceptible to accumulation of age‐related damage, whereas liver, testis, and lung were the least susceptible organs. DR prevented age‐related accumulation of mtDNA damage in the cortex and led to its decrease in the lung and testis. Changes in mtDNA copy number and expression of genes involved in the regulation of mitochondrial biogenesis and mitophagy were also tissue‐specific. There was a tendency for an age‐related decrease in the copy number of mtDNA in the striatum and its increase in the kidney. DR promoted an increase in the amount of mtDNA in the cerebellum and hippocampus. mtDNA damage may be associated not only with the metabolic activity of organs, but also with the lipid composition and activity of processes associated with the isoprostanes pathway of lipid peroxidation. The comparison of polyunsaturated fatty acids and oxylipin profiles in old rats showed that DR decreased the synthesis of arachidonic acid and its metabolites synthesized by the cyclooxygenase, cytochrome P450 monooxygenases and lipoxygenase metabolic pathways.

We investigated the nephroprotective effect of D-panthenol in rhabdomyolysis-induced acute kidney injury (AKI). Adult male Wistar rats were injected with 50% glycerol solution to induce rhabdomyolysis. Animals with rhabdomyolysis were injected with D-panthenol (200 mg/kg) for 7 days. On day 8, we examined AKI markers, renal histology, antioxidant capacity, and protein glutathionylation in kidneys to uncover mechanisms of D-panthenol effects. Rhabdomyolysis kidneys were shown to have pathomorphological alterations (mononuclear infiltration, dilatation of tubules, and hyaline casts in Henle’s loops and collecting ducts). Activities of skeletal muscle damage markers (creatine kinase and lactate dehydrogenase) increased, myoglobinuria was observed, and creatinine, BUN, and pantetheinase activity in serum and urine rose. Signs of oxidative stress in the kidney tissue of rhabdomyolysis rats, increased levels of lipid peroxidation products, and activities of antioxidant enzymes (SOD, catalase, and glutathione peroxidase) were all alleviated by administration of D-panthenol. Its application improved kidney morphology and decreased AKI markers. Mechanisms of D-panthenol’s beneficial effects were associated with an increase in total coenzyme A levels, activity of Krebs cycle enzymes, and attenuation of protein glutathionylation. D-Panthenol protects kidneys from rhabdomyolysis-induced AKI through antioxidant effects, normalization of mitochondrial metabolism, and modulation of glutathione-dependent signaling.

The changes in the parameters of oxidative stress, energy metabolism, and redox potential of the glutathione system in the rat brain following cerebral ischemia were studied. To correct metabolic disorders, the pantothenic acid derivatives were used in combination with precursors of glutathione biosynthesis and selenium substances.Cerebral ischemia was modeled by ligating the both common carotid arteries in rats for 2 h. Drugs were administered i.p. in the following doses: panthenol – 400 mg/kg, N-acetylcysteine – 150, nanoselen – 1 mg/kg, three times: 1 h before ligation of the carotid arteries, at the time of ligation and 1 hour after ligation. We showed that the development of oxidative stress caused by ischemia is accompanied by the changes in the parameters of energy metabolism and the pentose phosphate pathway in the cerebral hemispheres. Simultaneously, there are a decrease in the GSH level, an increase in the GSSG content, a decrease in the GSH/GSSG ratio, and the activation of enzymes of redox transformations of glutathione.The redox potential of the glutathione system decreases and shifts towards oxidation, while the level of S-glutathionylated proteins increases. Thus, the value of the GSH/GSSG ratio and the protein glutathionylation intensity are the sensitive indicators of the redox potential in the brain tissue and can be used as markers of the extent of changes in the redox balance. The panthenol injection to animals leads to a decrease in the content of free radical oxidation products, violations of oxidative phosphorylation and restoration of thiol-disulfide balance in the brain. When panthenol is administered together with N-acetylcysteine and nanoselen, the corrective effect of panthenol is enhanced.

Abstract—We studied changes in the indices of free-radical oxidation and thiol-disulfide status in the brain structures in the experimental model of Parkinson’s disease (PD) induced by administration of rotenone to rats. Pantothenic acid derivatives, such as panthenol (PL), pantethine (PT), and homopantothenic acid (HPA) were used as neuromodulators. It was found that redox imbalance in the brain induced by rotenone is accompanied by the activation of free-radical processes, pronounced inhibition of antioxidant defense, a considerable decrease in the glutathione system reduction potential, and increased protein glutathionylation. The strongest changes were in the basal ganglia of the brain. PL and PT but not HPA, decrease the changes in the free-radical oxidation and thiol-disulfide balance in the brain structures. During experimental neurotoxicosis, the mechanisms of neuroprotective action of PL and PT, which are linked with the changes in the biosynthesis of CoA, are, obviously, related to their ability to increase the reduction potential of the glutathione system, thus mitigating the effects of oxidative stress.

Using an experimental model of aluminum neurotoxicosis, it was established that under conditions of chronic administration of aluminum chloride to rats, oxidative stress develops and inhibits the redox potential of the glutathione system in the mitochondrial and postmitochondrial fractions of the cerebral hemispheres. It was shown that the ingestion of N-acetylcysteine, as well as its combined use with coenzyme A biosynthesis precursors (D-panthenol or D-pantetin) against the background of aluminum neurotoxicosis, leads to a marked decrease in the production of reactive oxygen species by mitochondria, a decrease in the production of thiobarbituric acid reactive substances, and normalization of GSH content and its biosynthesis in brain tissue. The results indicate a high efficiency of the biosynthesis precursor of glutathione N-acetylcysteine in the prevention of oxidative stress in the chronic model of aluminum neurotoxicosis, which may be the rationale for its use as a modulator of mitochondrial redox status in the development of neurodegenerative pathology.

We studied changes in S-glutathionylated proteins (PSSG) content in rat brain structures in different experimental models of neurodegenerative pathology, as well as the possibility of correcting these changes with pantothenic acid derivatives. We have shown that the content of PSSG significantly increases in brain structures in all the models of neurotoxicosis that we studied, and this increase is observed to the greatest extent precisely in those structures where a particular neurotoxin has the most pronounced effect. Thus, the content of PSSG is a sensitive marker of post-translational protein modification. Precursors of CoA reduce S-glutathionylation of proteins, since HPA, which is not a precursor of CoA, does not have a protective effect in relation to PSSG.

SOME PROBLEMS OF MEASUREMENT OF THIOLS AND DISULFIDES N CLINICAL MATERIAL REVIEW

Rapid development of multiple drug resistance and occurrence of negative side effects in cancer patients arising at the treatment belong to the main problems in cancer chemotherapy. Recently, it was shown that specific antioxidants (selenomethionine – SeMet and D-pantethine – D-Pt) possessed nephro-, myelo- and hepatoprotective activity at doxorubicin's (Dx) action in tumor-bearing mice. Besides, these antioxidants inhibited a cytotoxic action of Dx toward chemotherapy-sensitive tumor cells, and enhanced the cytotoxic effect of this drug toward selected drug-resistant tumor cell lines (e.g. HL-60/vinc, HL-60/adr), while in other such lines (e.g. HCT-116/Bax(−/−), HCT-116/p53), it was not effective. The aim of present study was to investigate the molecular mechanisms of the revealed difference in the action of SeMet and D-Pt toward cytotoxic effects of Dx in tumor cells varying in drug resistance. Human leukemia cells of HL-60/wt line and its drug-resistant sublines HL-60/adr (overexpression of MRP-1) and HL-60/vinc (overexpression of P-gp) were used in this study. Treatment of cells with Dx led to the versatile action of this drug on the level of glutathione in each of the studied cell line and sublines. HL-60/wt cells were characterized by 8-fold lower GSH level under Dx treatment compared to control, while in HL-60/vinc and HL-60/adr cells GSH level was increased 2.2- and 8.2-fold (compared to untreated cells), correspondingly. The use of doxorubicin also led to significant rearrangement of GSSG/GSH ratio in these cell lines, leading to 2-fold elevation of GSSG level HL-60/vinc cells, and 2.5-fold decrease of this index in HL-60/adr cells. We have shown that a combined effect of SeMet or D-Pt on the background of the cytotoxic action of doxorubicin on HL-60/vinc cells is accompanied by a 2-fold decrease in both oxidized and reduced glutathione levels. Such an effect of these antioxidants can serve as an explanation of their sensitizing effect on the cells of the HL-60/vinc subline under Dx's action which we observed earlier. It should be noted that treatment with Dx led to a 2.5-fold increase in the activity of glutathione-S-transferase in the leukemia cells of HL-60/vinc subline. The antioxidants effectively reduced this indicator. SeMet and D-Pt differentialy affected the activity of glutathione-S-transferase in HL-60/adr cells. In conclusion, our data demonstrate an important role of the antioxidants on the functional state of the glutathione system in tumor cells that differ in their drug resistance. The obtained results suggest an important role of glutathione-S-transferase in modulation of cancer drug resistance that is caused by P-glycoprotein overexpression, but not by the overexpression of MRP-1 protein. Selenomethionine and D-pantethine effectively inhibit this enzyme, thus, sensitizing P-gp overexpressing cells towards the action of doxorubicin. This event is accompanied by further decrease in GSH and GSSG levels in these cells, thus sensitizing them to Dx action. Further studies of the molecular mechanisms underlying this phenomenon are in progress.