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Chemosensitizing activity of histone deacetylases inhibitory cyclic hydroxamic acids for combination chemotherapy of lymphatic leukemia

dc.contributor.authorMishchenko D.V.
dc.contributor.authorNeganova M.E.
dc.contributor.authorKlimanova E.N.
dc.contributor.authorSashenkova T.E.
dc.contributor.authorKlochkov S.G.
dc.contributor.authorShevtsova E.F.
dc.contributor.authorVystorop I.V.
dc.contributor.authorTarasov V.V.
dc.contributor.authorChubarev V.N.
dc.contributor.authorSamsonova A.N.
dc.contributor.authorAshraf G.M.
dc.contributor.authorBarreto G.
dc.contributor.authorYarla N.S.
dc.contributor.authorAliev G.
dc.date.accessioned2020-09-02T22:23:03Z
dc.date.available2020-09-02T22:23:03Z
dc.date.issued2018
dc.identifier10.2174/1568009617666170623104030
dc.identifier.citation18, 4, 365-371
dc.identifier.issn15680096
dc.identifier.urihttps://hdl.handle.net/20.500.12728/5350
dc.descriptionBackground: Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis. Objective: The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents. Method: Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study. Results: Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine<Alanine<Valine<Leucine <Phenylalanine). All compounds bearing spiro-N-methylpiperidine ring (2a-e) are non-toxic up to 1250 mg/kg dose, while compounds bearing spiro-tetramethylpiperidine ring (1a-e) exhibit moderate toxicity which increases with increasing lipophility, but not excite at 400 mg/kg. Conclusion: It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia Р388 is demonstrated by the CHA derivatives of Valine 1c or 2c. © 2018 Bentham Science Publishers.
dc.language.isoen
dc.publisherBentham Science Publishers B.V.
dc.subjectChemosensitizing property
dc.subjectCombination chemotherapy
dc.subjectHDAC inhibitory activity
dc.subjectHistone deacetylases
dc.subjectHydroxamic acid
dc.subjectLymphatic leukemia
dc.subjectcyclophosphamide
dc.subjectferrozine
dc.subjecthistone deacetylase inhibitor
dc.subjecthydroxamic acid
dc.subjecttrichostatin A
dc.subjectantineoplastic agent
dc.subjecthistone deacetylase inhibitor
dc.subjecthydroxamic acid
dc.subjectacute toxicity
dc.subjectanimal experiment
dc.subjectantineoplastic activity
dc.subjectArticle
dc.subjectchemosensitivity
dc.subjectcontrolled study
dc.subjectdrug structure
dc.subjectdrug therapy
dc.subjectiron chelation
dc.subjectLD50
dc.subjectlipid peroxidation
dc.subjectlipophilicity
dc.subjectlymphatic leukemia
dc.subjectmale
dc.subjectmetastasis inhibition
dc.subjectnonhuman
dc.subjectoxidative stress
dc.subjectrat
dc.subjectanimal
dc.subjectchemistry
dc.subjectHeLa cell line
dc.subjecthuman
dc.subjectlymphatic leukemia
dc.subjectmetabolism
dc.subjectmouse
dc.subjectpathology
dc.subjectAnimals
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectHeLa Cells
dc.subjectHistone Deacetylase Inhibitors
dc.subjectHumans
dc.subjectHydroxamic Acids
dc.subjectLeukemia, Lymphoid
dc.subjectMale
dc.subjectMice
dc.subjectRats
dc.titleChemosensitizing activity of histone deacetylases inhibitory cyclic hydroxamic acids for combination chemotherapy of lymphatic leukemia
dc.typeArticle


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