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

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 H 2 O 2 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.

P-I metalloproteinases and L-amino acid oxidases from Bothrops species inhibit angiogenesis

“…Further, Stábeli et al [ 54 ] isolated LAAO (64.8 kDa) from B. moojeni by ion-exchange chromatography and phenyl-sepharose chromatography. The LAAO isolated from both B. moojeni and B. atrox in the present study exhibited molecular mass of ~58 kDa protein as observed on SDS PAGE which is in the agreement with the previous studies [ 32 , 54 , 55 ].…”

P-I metalloproteinases and L-amino acid oxidases from Bothrops species inhibit angiogenesis

“…Further, Stábeli et al [ 54 ] isolated LAAO (64.8 kDa) from B. moojeni by ion-exchange chromatography and phenyl-sepharose chromatography. The LAAO isolated from both B. moojeni and B. atrox in the present study exhibited molecular mass of ~58 kDa protein as observed on SDS PAGE which is in the agreement with the previous studies [ 32 , 54 , 55 ].…”

A Complex Pattern of Gene Expression in Tissue Affected by Viperid Snake Envenoming: The Emerging Role of Autophagy-Related Genes

“…Bothrops sp. venom components have been shown to induce apoptosis and autophagy of various cell types in culture [ 54 , 55 , 56 , 57 ]. The genes BIRC3 and BCL2L1 were up-regulated in tissue injected with the two venoms.…”

Integrated Chemical Characterization, Network Pharmacology and Transcriptomics to Explore the Mechanism of Sesquiterpenoids Isolated from Gynura divaricata (L.) DC. against Chronic Myelogenous Leukemia

“…One of the hallmarks of CML is the deregulation of apoptosis [39,40]. Therefore, the effect of GD-NAIs on the apoptosis of K562 cells was verified.…”

“…We thus monitored the effect of GD-NAIs on the proliferation of K562 cells and observed that GD-NAIs conspicuously suppressed the proliferation of K562 cells in a concentration-dependent manner. Another hallmark of CML is a defect in apoptosis [39,40]. We found that GD-NAIs could induce apoptosis of K562 cells.…”

P-I metalloproteinases and L-amino acid oxidases from Bothrops species inhibit angiogenesis

“…Further, Stábeli et al [ 54 ] isolated LAAO (64.8 kDa) from B. moojeni by ion-exchange chromatography and phenyl-sepharose chromatography. The LAAO isolated from both B. moojeni and B. atrox in the present study exhibited molecular mass of ~58 kDa protein as observed on SDS PAGE which is in the agreement with the previous studies [ 32 , 54 , 55 ].…”

A Complex Pattern of Gene Expression in Tissue Affected by Viperid Snake Envenoming: The Emerging Role of Autophagy-Related Genes

“…Bothrops sp. venom components have been shown to induce apoptosis and autophagy of various cell types in culture [ 54 , 55 , 56 , 57 ]. The genes BIRC3 and BCL2L1 were up-regulated in tissue injected with the two venoms.…”

Integrated Chemical Characterization, Network Pharmacology and Transcriptomics to Explore the Mechanism of Sesquiterpenoids Isolated from Gynura divaricata (L.) DC. against Chronic Myelogenous Leukemia

“…One of the hallmarks of CML is the deregulation of apoptosis [39,40]. Therefore, the effect of GD-NAIs on the apoptosis of K562 cells was verified.…”

“…We thus monitored the effect of GD-NAIs on the proliferation of K562 cells and observed that GD-NAIs conspicuously suppressed the proliferation of K562 cells in a concentration-dependent manner. Another hallmark of CML is a defect in apoptosis [39,40]. We found that GD-NAIs could induce apoptosis of K562 cells.…”

P-I metalloproteinases and L-amino acid oxidases from Bothrops species inhibit angiogenesis

“…Further, Stábeli et al [ 54 ] isolated LAAO (64.8 kDa) from B. moojeni by ion-exchange chromatography and phenyl-sepharose chromatography. The LAAO isolated from both B. moojeni and B. atrox in the present study exhibited molecular mass of ~58 kDa protein as observed on SDS PAGE which is in the agreement with the previous studies [ 32 , 54 , 55 ].…”

A Complex Pattern of Gene Expression in Tissue Affected by Viperid Snake Envenoming: The Emerging Role of Autophagy-Related Genes

“…Bothrops sp. venom components have been shown to induce apoptosis and autophagy of various cell types in culture [ 54 , 55 , 56 , 57 ]. The genes BIRC3 and BCL2L1 were up-regulated in tissue injected with the two venoms.…”

Integrated Chemical Characterization, Network Pharmacology and Transcriptomics to Explore the Mechanism of Sesquiterpenoids Isolated from Gynura divaricata (L.) DC. against Chronic Myelogenous Leukemia

“…One of the hallmarks of CML is the deregulation of apoptosis [39,40]. Therefore, the effect of GD-NAIs on the apoptosis of K562 cells was verified.…”

“…We thus monitored the effect of GD-NAIs on the proliferation of K562 cells and observed that GD-NAIs conspicuously suppressed the proliferation of K562 cells in a concentration-dependent manner. Another hallmark of CML is a defect in apoptosis [39,40]. We found that GD-NAIs could induce apoptosis of K562 cells.…”