L‐Amino Acid Oxidase Isolated from Bothrops pirajai Induces Apoptosis in BCR‐ABL‐Positive Cells and Potentiates Imatinib Mesylate Effect

Abstract

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.