6 research outputs found
Antioxidants selenomethionine and D-pantethine decrease the negative side effects of doxorubicin in NL/Ly lymphoma-bearing mice
Aim To investigate the potential tissue-protective effects
of antioxidants selenomethionine and D-pantethine applied
together with doxorubicin (Dx) on NK/Ly lymphomabearing
mice. The impact of this chemotherapy scheme
on animal survival, blood cell profile, hepatotoxicity, glutathione
level, and activity of glutathione-converting enzymes
in the liver was compared with the action of Dx applied
alone.
Methods The hematological profile of animals was studied
by the analysis of blood smears under light microscopy.
Hepatotoxicity of studied drugs was evaluated measuring
the activity of alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) enzymes, De Ritis ratio, and coenzyme
A fractions by McDougal assay. Glutathione level in
animal tissues was measured with Ellman reagent, and the
activity of glutathione reductase, transferase, and peroxidase
was measured using standard biochemical assays.
Results D-pantethine (500 mg/kg) and, to a lower extent,
selenomethionine (600 μg/kg) partially reduced the negative
side effects (leukocytopenia and erythropenia) of Dx (5
mg/kg) in NK/Ly lymphoma bearing animals on the 14th
day of their treatment. This increased animal survival time
from 47-48 to 60+ days and improved the quality of their
life. This ability of D-pantethine and selenomethionine was
realized via hepatoprotective and immunomodulating activities.
D-pantethine also restored the levels of acid-soluble
and free CoA in the liver of tumor-bearing animals,
while selenomethionine caused the recovery of glutathione
peroxidase levels in the liver, which was significantly
diminished under Dx treatment. Both compounds decreased
glutathione level in the liver, which was considerably
induced by Dx.
Conclusions Antioxidants selenomethionine and D-pantethine
partially reversed the negative side effects of Dx in
NK/Ly lymphoma-bearing mice and significantly increased
the therapeutic efficiency of this drug in tumor treatment
Landomycins as Glutathione-Depleting Agents and Natural Fluorescent Probes for Cellular Michael Adduct-Dependent Quinone Metabolism
Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria. The aglycone landomycinone is the distinctive core, while the oligosaccharide chain differs within derivatives. Herein, we report that landomycins spontaneously form Michael adducts with biothiols, including reduced cysteine and glutathione, both cell-free or intracellularly involving the benz[a]anthraquinone moiety of landomycinone. While landomycins generally do not display emissive properties, the respective Michael adducts exerted intense blue fluorescence in a glycosidic chain-dependent manner. This allowed label-free tracking of the short-lived nature of the mono-SH-adduct followed by oxygen-dependent evolution with addition of another SH-group. Accordingly, hypoxia distinctly stabilized the fluorescent mono-adduct. While extracellular adduct formation completely blocked the cytotoxic activity of landomycins, intracellularly it led to massively decreased reduced glutathione levels. Accordingly, landomycin E strongly synergized with glutathione-depleting agents like menadione but exerted reduced activity under hypoxia. Summarizing, landomycins represent natural glutathione-depleting agents and fluorescence probes for intracellular anthraquinone-based angucycline metabolism
Putative anticancer potential of novel 4-thiazolidinone derivatives: cytotoxicity toward rat C6 glioma in vitro and correlation of general toxicity with the balance of free radical oxidation in rats
Aim To evaluate the cytotoxic action of 4-thiazolidinone derivatives
(ID 3288, ID 3882, and ID 3833) toward rat glioma
C6 cells and to compare the effects of these compounds
and doxorubicin on the balance of free radical oxidation
(FRO) and antioxidant activity (AOA) in the serum of rats.
Methods Glioma cells were treated with ID 3882, ID 3288,
ID 3833, and doxorubicin, and their cytotoxicity was studied
using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) assay and Trypan blue exclusion test, light
and fluorescent microscopy, and flow cytometric study of
cell cycling and apoptosis, including measuring of Annexin
V-positive cells. The contents of superoxide radical, hydrogen
peroxide, hydroxyl radical, malonic dialdehyde, and hydrogen
sulfide were measured in the serum of rats. Enzymatic
activity of superoxide dismutase (SOD), catalase (Cat),
and glutathione peroxydase (GPO) was determined.
Results Among novel 4-thiazolidinone derivatives, ID 3288
was most toxic toward rat glioma C6 cells, even compared
with doxorubicin. All applied derivatives were less active
than doxorubicin in inducing reactive oxygen species-related
indicators in the serum of rats. A similar effect was observed
when enzymatic indicators of AOA processes were
measured. While doxorubicin inhibited the activity of SOD,
GPO, and Cat, the effects of 4-thiazolidinone derivatives
were less prominent.
Conclusion Novel 4-thiazolidinone derivatives differ in their
antineoplastic action toward rat glioma C6 cells, and ID 3288
possesses the highest activity compared to doxorubicin.
Measurement of indicators of FRO and AOA in the serum of
rats treated with these compounds showed their lower general
toxicity compared with doxorubicin’s toxicity
Complex of C60 fullerene with doxorubicin as a promising agent in antitumor therapy
The main aim of this work was to evaluate the effect of doxorubicin in complex with C60 fullerene (C60 + Dox) on the growth and metastasis of Lewis lung carcinoma in mice and to perform a primary screening of the potential mechanisms of C60 + Dox complex action. We found that volume of tumor from mice treated with the C60 + Dox complex was 1.4 times less than that in control untreated animals. The number of metastatic foci in lungs of animals treated with C60 + Dox complex was two times less than that in control untreated animals. Western blot analysis of tumor lysates revealed a significant decrease in the level of heat-shock protein 70 in animals treated with C60 + Dox complex. Moreover, the treatment of tumor-bearing mice was accompanied by the increase of cytotoxic activity of immune cells. Thus, the potential mechanisms of antitumor effect of C60 + Dox complex include both its direct action on tumor cells by inducing cell death and increasing of stress sensitivity and an immunomodulating effect. The obtained results provide a scientific basis for further application of C60 + Dox nanocomplexes as treatment agents in cancer chemotherapy