L-amino acid oxidase induces apoptosis and epigenetic modulation on Bcr-Abl cells.

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 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 .

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 and and downregulated expression in leukemic cell lines, as well as increased miR-16 expression - whose major predicted target is the anti-apoptotic gene - in Bcr-Abl cells.

Conclusion: BmooLAAO-I exerts selective antitumor action mediated by HO release and induces apoptosis, and alterations in epigenetic mechanisms. These results support future investigations on the effect of BmooLAAO-I on models to determine its potential in CML therapy.