Tag Archives: 4-thiazolidinone derivatives

Targeting of the pro-oxidant-antioxidant balance in vitro and in vivo by 4-thiazolidinone-based chemotherapeutics with anticancer potential

L. Kobylinska1, O. Klyuchivska2, R. Lesyk1, R. Stoika2

1Danylo Halytsky Lviv National Medical University, Ukraine;
2Institute of Cell Biology, Lviv, Ukraine;
e-mail: lesya8@gmail.com

Received: 05 January 2019; Accepted: 20 March 2019

Oxidative stress is one of the main mechanisms by which anticancer chemotherapeutics damage normal tissues and organs. At the same time, it is an important biochemical mechanism of the neoplastic action of such medicines. The aim of the present study was to determine the pro-oxidant-antioxidant balance in vitro and in vivo under the influence of novel 4-thiazolidinone-based chemotherapeutics with anticancer potential. An advantage of using these compounds in vivo is their low general toxicity, compared to doxorubicin (Kobylinska L. et al., 2014, 2015, 2016). The 4-thiazolidinone derivatives (Les-3288, Les-3833, Les-3882) with previously established anti-neoplastic activity in vitro (Kobylinska L. et al., 2016) and antitumor effect in vivo (Kobylinska L. et al., 2018) were synthesized, dissolved in dimethyl sulfoxide, and administered intraperitoneally to Wistar rats daily for 20 days. Doses of the injected drugs equaled 10% of the LD50, namely doxorubicin – 5.5 mg/kg, Les-3882 and Les-3833 – 10.7 mg/kg, and Les-3288 – 24.3 mg/kg. The radical scavenging of 1,1-diphenyl-2-picrylhydrazil (DPPH) activity was measured. Concentrations of thio-barbituric acid-active products were assessed in blood serum, liver, heart and kidney tissues of treated rats. Additionally, the activities of superoxide dismutase, catalase and glutathione peroxidase were measured in blood serum and these tissues. We found that administration for 20 days of Les-3288, Les-3833 and Les-3882 compounds disturbed the pro-oxidant-antioxidant balance in the treated rats. Increased amounts of products of reactions of lipid peroxidation and exhaustion of the enzymatic antioxidant system in liver, heart and kidney tissues were detected. In general, Les-3288, Les-3833 and Les-3882 compounds exhibited less pro-oxidant action, compared with the effect of doxorubicin. According to the results of influencing the pro-oxidant-antioxidant balance in the selected tissues, the studied compounds can be ranked in the following order: doxorubicin >> Les-3833 > Les-3288 >> Les-3882. The results of measuring direct scavenging ability of these compounds observed in 24 h suggests their lower toxic effect compared with the effect of the doxorubicin. The obtained results are in correspondence with the results of our recent experiments demonstrating their antineoplastic effect in vitro (Kobylinska L. et al., 2016) and anticancer action in vivo (Kobylinska L. et al., 2018), as well as their lower general toxicity in vivo compared with doxorubicin (Kobylinska L. et al., 2014, 2015, 2016).

4-Thiazolidinone-based derivatives rescue TNAα-inhibited osteoblast differentiation in mouse mesenchymal precursor cells

Kh. V. Malysheva1,2,3, N. S. Finiuk1, O. K. Pavlenko4, D. Ya. Havrylyuk5,
R. B. Lesyk5, R. S. Stoika1, O. G. Korchynskyi1,3

1Institute of Cell Biology, NAS of Ukraine, Lviv;
2Insitute of Animal Biology, NAAS of Ukraine, Lviv;
3Centre for Innovative Research in Medical and Natural Sciences,
Rzeszow University and Medical Faculty, Poland;
4Ivan Franko National University of Lviv, Ukraine;
5Danylo Halytsky Lviv National Medical University, Ukraine;
e-mail: olexkor@hotmail.com

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease of yet unknown etiology. Tumor necrosis factor α (TNFα) is recognized as a regulatory substance that plays a central role in RA development and progression. On the other side, the bone morphogenetic protein (BMP) and Wnt signaling pathways are key mechanisms that induce and support cartilage and bone formation and maintenance. Previous studies showed that the pro-inflammatory cytokines TNFα and interleukin 1β (IL-1β) are central players in the inhibition of activity of skeletogenesis. The aim of this study was to evaluate the anti-inflammatory activity of novel 4-thiazolidinone-based derivatives towards TNFα–induced pro-inflammatory effects during bone formation. We performed in vitro evaluation of functional effects of 4-thiazolidinones denoted as Les-4368, Les-4370, Les-3882 and Les-3288 that were used in different doses (0.02, 0.1, 0.3 and 1.0 μM) on the TNFα-mediated inhibition of the BMP-induced osteoblast differentiation in mouse mesenchymal precursor (stem) cells of C2C12 line. Treatment of these cells with TNFα completely inhibited their myogenic differentiation, as well as strongly inhibited the BMP-induced osteogenesis. Strikingly, the treatment of C2C12 cells with Les-4368 and Les-3882 rescued the osteoblast differentiation from negative control of TNFα, and, moreover, converted this cytokine from the inhibitor of osteogenesis into its stimulator. Western-blot analysis of Inhibitory κBα (I-κBα) degradation was used to elucidate a mechanism of the anti-inflammatory effects. Les-3882 was more active, and it stimulated osteoblast differentiation at low dose (0.1 μM), presumably, via modulation of the NF-κB signaling pathway.

Biochemical indicators of nephrotoxicity in blood serum of rats treated with novel 4-thiazolidinone derivatives or their complexes with polyethylene glycol-containing nanoscale polymeric carrier

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

 1Danylo Halytsky Lviv National Medical University, Ukraine;
e-mail: stoika@cellbiol.lviv.ua;
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-thiazolidinone derivatives (potential anticancer compounds denoted as 3882, 3288 and 3833) and doxorubicin (positive control) in free form and in their complexes with synthetic polyethylene glycol-containing nanoscale polymeric carrier on the biochemical indicators of nephrotoxicity in blood serum of rats. The concentration of total protein, urea, creatinine, glucose, ions of sodium, potassium, calcium, iron and chloride was measured. It was found that after injection of the investigated compounds, the concentration of sodium cations and chloride anions in blood serum was increased compared with control (untreated animals). Doxorubicin’s injection was accompanied by a decrease in the concentration of iron cations. The concentration of total protein, urea and creatinine decreased under the influence of the studied compounds. Complexation of these аntineoplastic substances with a synthetic polymeric nanocarrier lowered the concentration of the investigated metabolites substantially compared to the effect of these compounds in free form. The normalization of concentration of total protein, urea and creatinine in blood serum of rats treated with complexes of the studied compounds with the polymeric carrier comparing with increased concentration of these indicators at the introduction of such compounds in free form was found.

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.