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Bothrops moojeni L-amino acid oxidase induces apoptosis and epigenetic modulation on Bcr-Abl+ cells
Burin, Sandra Mara; Cacemiro, Maira da Costa; Cominal, Juçara Gastaldi; Grandis, Rone Aparecido De; Machado, Ana Rita Thomazela; Donaires, Flavia Sacilotto; Cintra, Adelia Cristina Oliveira; Ambrosio, Luciana; Antunes, Lusânia Maria Greggi; Sampaio, Suely Vilela; Castro, Fabíola Attié de.
  • Burin, Sandra Mara; University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences. Ribeirão Preto. BR
  • Cacemiro, Maira da Costa; University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences. Ribeirão Preto. BR
  • Cominal, Juçara Gastaldi; University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences. Ribeirão Preto. BR
  • Grandis, Rone Aparecido De; University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences. Ribeirão Preto. BR
  • Machado, Ana Rita Thomazela; University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences. Ribeirão Preto. BR
  • Donaires, Flavia Sacilotto; University of São Paulo. Ribeirão Preto Medical School. Department of Internal Medicine. Ribeirão Preto. BR
  • Cintra, Adelia Cristina Oliveira; University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences. Ribeirão Preto. BR
  • Ambrosio, Luciana; University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences. Ribeirão Preto. BR
  • Antunes, Lusânia Maria Greggi; University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences. Ribeirão Preto. BR
  • Sampaio, Suely Vilela; University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences. Ribeirão Preto. BR
  • Castro, Fabíola Attié de; University of São Paulo. School of Pharmaceutical Sciences. Department of Clinical Analyses, Toxicology and Food Sciences. Ribeirão Preto. BR
J. venom. anim. toxins incl. trop. dis ; 26: e20200123, 2020. graf
Article in English | LILACS, VETINDEX | ID: biblio-1143219
ABSTRACT
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)
Subject(s)


Full text: Available Index: LILACS (Americas) Main subject: Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Apoptosis / Bothrops / L-Amino Acid Oxidase Type of study: Prognostic study Limits: Animals Language: English Journal: J. venom. anim. toxins incl. trop. dis Year: 2020 Type: Article Institution/Affiliation country: University of São Paulo/BR

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Full text: Available Index: LILACS (Americas) Main subject: Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Apoptosis / Bothrops / L-Amino Acid Oxidase Type of study: Prognostic study Limits: Animals Language: English Journal: J. venom. anim. toxins incl. trop. dis Year: 2020 Type: Article Institution/Affiliation country: University of São Paulo/BR