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

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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]

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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

• Tipo de documento: Artigo Científico
• Fonte: Journal of Venomous Animals and Toxins including Tropical Diseases; v. 26, 2020-12-14.

Resumo

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)

• Processo FAPESP: 18/01756-5 - Caracterização Imunológica e Funcional das Células Estromais Mesenquimais Multipotentes em Neoplasias Mieloproliferativas
• Beneficiário: Maira da Costa Cacemiro
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 11/23236-4 - Toxinas animais nativas e recombinantes: análise funcional, estrutural e molecular
• Beneficiário: Suely Vilela
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/25637-7 - Modulação epigenética da maquinaria apoptótica em células Bcr-Abl positivas pelas toxinas BmooLAAO-I e MjTX-I
• Beneficiário: Sandra Mara Burin de Menezes
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado