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

• Published in: Journal of Venomous Animals and Toxins including Tropical Diseases
• Main Authors: Sandra Mara Burin, Maira da Costa Cacemiro, Juçara Gastaldi Cominal, Rone Aparecido De Grandis, Ana Rita Thomazela Machado, Flavia Sacilotto Donaires, Adelia Cristina Oliveira Cintra, Luciana Ambrosio, Lusânia Maria Greggi Antunes, Suely Vilela Sampaio, Fabíola Attié de Castro
• Format: Article in Journal/Newspaper
• Language: English
• Published: SciELO 2020
• Subjects: Apoptosis; MicroRNA; Chronic myeloid leukemia; Snake toxins; BmooLAAO-I; Bothrops moojeni; Arctic medicine. Tropical medicine; RC955-962; Toxicology. Poisons; RA1190-1270; Zoology; QL1-991; Arctic
• Online Access: https://doi.org/10.1590/1678-9199-jvatitd-2020-0123; https://doaj.org/article/009b2f7e59444a198e0bfae03b783f35

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.