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(Reference retrieved automatically from SciELO through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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Sandra Mara Burin [1] ; Maira da Costa Cacemiro [2] ; Juçara Gastaldi Cominal [3] ; Rone Aparecido De Grandis [4] ; Ana Rita Thomazela Machado [5] ; Flavia Sacilotto Donaires [6] ; Adelia Cristina Oliveira Cintra [7] ; Luciana Ambrosio [8] ; Lusânia Maria Greggi Antunes [9] ; Suely Vilela Sampaio [10] ; Fabíola Attié de Castro [11]
Total Authors: 11
Affiliation:
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[1] University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences - Brasil
[2] University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences - Brasil
[3] University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences - Brasil
[4] University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences - Brasil
[5] University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences - Brasil
[6] University of São Paulo. Ribeirão Preto Medical School. Department of Internal Medicine - Brasil
[7] University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences - Brasil
[8] University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences - Brasil
[9] University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences - Brasil
[10] University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences - Brasil
[11] University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences - Brasil
Total Affiliations: 11
Document type: Journal article
Source: Journal of Venomous Animals and Toxins including Tropical Diseases; v. 26, 2020-12-14.
Abstract

Abstract 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 H2O2 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. (AU)

FAPESP's process: 18/01756-5 - Immunological and Functional Characterization of Multipotent Mesenchymal Stromal Cells in Myeloproliferative Neoplasms
Grantee:Maira da Costa Cacemiro
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 11/23236-4 - Native and recombinant animal toxins: functional, structural and molecular analysis
Grantee:Suely Vilela
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 15/25637-7 - Epigenetic modulation of apoptotic machinery in Bcr-Abl positive cells by BmooLAAO-I and MjTX-I toxins
Grantee:Sandra Mara Burin de Menezes
Support Opportunities: Scholarships in Brazil - Post-Doctoral