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

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Burin, Sandra Mara ^[1] ; Cacemiro, Maira Costa ^[1] ; Cominal, Jucara Gastaldi ^[1] ; De Grandis, Rone Aparecido ^[1] ; Thomazela Machado, Ana Rita ^[1] ; Donaires, Flavia Sacilotto ^[2] ; Oliveira Cintra, Adelia Cristina ^[1] ; Ambrosio, Luciana ^[1] ; Greggi Antunes, Lusania Maria ^[1] ; Sampaio, Suely Vilela ^[1] ; de Castro, Fabiola Attie ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin Anal Toxicol & Food Sci, Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Venomous Animals and Toxins including Tropical Diseases; v. 26, DEC 14 2020.
• Citações Web of Science: 0

Resumo

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: 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
• 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: 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