Bothrops moojeni L-amino acid oxidase induces apoptosis and epigenetic modulation on Bcr-Abl + cells.

Autor: Burin SM; Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences, University of São Paulo (USP), Ribeirão Preto, SP, Brazil., Cacemiro MDC; Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences, University of São Paulo (USP), Ribeirão Preto, SP, Brazil., Cominal JG; Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences, University of São Paulo (USP), Ribeirão Preto, SP, Brazil., Grandis RA; Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences, University of São Paulo (USP), Ribeirão Preto, SP, Brazil., Machado ART; Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences, University of São Paulo (USP), Ribeirão Preto, SP, Brazil., Donaires FS; Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, Brazil., Cintra ACO; Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences, University of São Paulo (USP), Ribeirão Preto, SP, Brazil., Ambrosio L; Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences, University of São Paulo (USP), Ribeirão Preto, SP, Brazil., Antunes LMG; Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences, University of São Paulo (USP), Ribeirão Preto, SP, Brazil., Sampaio SV; Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences, University of São Paulo (USP), Ribeirão Preto, SP, Brazil., de Castro FA; Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences, University of São Paulo (USP), Ribeirão Preto, SP, Brazil.
Jazyk: angličtina
Zdroj: The journal of venomous animals and toxins including tropical diseases [J Venom Anim Toxins Incl Trop Dis] 2020 Dec 14; Vol. 26, pp. e20200123. Date of Electronic Publication: 2020 Dec 14.
DOI: 10.1590/1678-9199-JVATITD-2020-0123
Abstrakt: Background: Resistance to apoptosis in chronic myeloid leukemia (CML) is associated with constitutive tyrosine kinase activity of the Bcr-Abl oncoprotein. The deregulated expression of apoptosis-related genes and alteration in epigenetic machinery may also contribute to apoptosis resistance in CML. Tyrosine kinase inhibitors target the Bcr-Abl oncoprotein and are used in CML treatment. The resistance of CML patients to tyrosine kinase inhibitors has guided the search for new compounds that may induce apoptosis in Bcr-Abl + leukemic cells and improve the disease treatment.
Methods: In the present study, we investigated whether the L-amino acid oxidase isolated from Bothrops moojeni snake venom (BmooLAAO-I) (i) was cytotoxic to Bcr-Abl + cell lines (HL-60.Bcr-Abl, K562-S, and K562-R), HL-60 (acute promyelocytic leukemia) cells, the non-tumor cell line HEK-293, and peripheral blood mononuclear cells (PBMC); and (ii) affected epigenetic mechanisms, including DNA methylation and microRNAs expression in vitro .
Results: BmooLAAO-I induced ROS production, apoptosis, and differential DNA methylation pattern of regulatory apoptosis genes. The toxin upregulated expression of the pro-apoptotic genes BID and FADD and downregulated DFFA expression in leukemic cell lines, as well as increased miR-16 expression - whose major predicted target is the anti-apoptotic gene BCL2 - in Bcr-Abl + cells.
Conclusion: BmooLAAO-I exerts selective antitumor action mediated by H 2 O 2 release and induces apoptosis, and alterations in epigenetic mechanisms. These results support future investigations on the effect of BmooLAAO-I on in vivo models to determine its potential in CML therapy.
Competing Interests: Competing interests: The authors report no conflicts of interest.
Databáze: MEDLINE
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