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Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by the presence of Philadelphia chromosome and by BCR-ABL1, which encodes the BCR-ABL oncoprotein. Although imatinib mesylate (IM) is effective for CML treatment, patients in accelerated and blastic phases of the disease are often refractory to this therapy, and there are also cases of IM resistance in patients in the chronic phase. Therefore, potential new drugs are being investigated to improve the efficiency of the therapy of CML such as snake venoms and their compounds. In this investigation, Bothrops pirajai L-amino acid oxidase (BpirLAAO-I) effect on normal peripheral blood mononuclear cells (PBMC) and on BCR-ABL + cell line was assessed to explore its potential against leukaemic cells. MTT viability assay, lymphocyte subsets quantification and cell activation markers expression were performed to evaluate BpirLAAO-I effect on normal PBMC. The effect of BpirLAAO-I on HL-60 and HL-60.BCR-ABL cell lines was assessed by apoptosis detection. BpirLAAO-I was able to induce apoptosis in HL-60 and HL-60.BCR-ABL cell lines in a dose-dependent manner, promoted caspases 3, 8 and 9 activation and enhanced IM effect while not affecting the viability of normal cells. In addition, BpirLAAO-I promoted immune cells activation and lymphocytes subsets changes on normal PBMC. The results indicate that BpirLAAO-I induces apoptosis and potentiates IM effect on BCR-ABL + cells.Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by the presence of Philadelphia chromosome (Ph) and by BCR-ABL1 neogene, which encodes BCR-ABL oncoprotein. BCR-ABL presents a constitutive tyrosine kinase (TK) activity which is responsible for the resistance of BCR-ABL-positive cells to apoptosis and CML pathogenesis [1][2][3]. Apoptosis could be triggered by intrinsic (also referred to mitochondrial) and extrinsic pathways. The intrinsic pathway is related to release of cytochrome c from mitochondria followed by caspase-9 and caspase-3 activation [4,5], while extrinsic pathway involves death receptors stimulation followed by caspase-8 and caspase-3 triggering without direct involvement of mitochondria [5][6][7]. Studies showed that BCR-ABL expression in myeloid cells contributes to block intrinsic and extrinsic apoptosis pathways [8,9]. Chronic myeloid leukaemia treatments are chemotherapy (hydroxycarbamide), interferon-a and therapies that modulate antileukaemic immune response such as allogeneic bone marrow transplantation and donor lymphocyte infusion [10,11] and tyrosine kinase inhibitors (TKIs). In 2001, the TKI imatinib mesylate (IM) revolutionized CML treatment, becoming the standard first-line therapy [12]. Imatinib mesylate presents high activity in patients with CML at chronic phase inducing over 95% of complete haematological response and 73% of complete cytogenetic remission [13]. Imatinib mesylate therapy is effective, but imatinib-resistant cell clones have already been described and patients treated in disease advanced phase...

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Background: Breast cancer is the neoplasm with both the highest incidence and mortality rate among women worldwide. Given the known snake venom cytotoxicity towards several tumor types, we evaluated the effects of BthTX-I from Bothrops jararacussu on MCF7, SKBR3, and MDAMB231 breast cancer cell lines. Methods: BthTX-I cytotoxicity was determined via MTT [3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazoliumbromide] assay. Cell death was measured by a hypotonic fluorescent solution method, annexin-V-FITC/propidium iodide staining and by apoptotic/autophagic protein expression. Cancer stem cells (CSCs) were quantified by flow cytometry using anti-CD24-FITC and anti-CD44-APC antibodies and propidium iodide. Results: BthTX-I at 102 µg/mL induced cell death in all cell lines. The toxin induced apoptosis in MCF7, SKBR3, and MDAMB231 in a dose-dependent manner, as confirmed by the increasing number of hypodiploid nuclei. Expression of pro-caspase 3, pro-caspase 8 and Beclin-1 proteins were increased, while the level of the antiapoptotic protein Bcl-2 was diminished in MCF7 cells. BthTX-I changed the staining pattern of CSCs in MDAMB231 cells by increasing expression of CD24 receptors, which mediated cell death. Conclusions: BthTX-I induces apoptosis and autophagy in all breast cancer cell lines tested and also reduces CSCs subpopulation, which makes it a promising therapeutic alternative for breast cancer.