Cytotoxic and pro-apoptotic action of MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, towards leukemic cells

Autor(es)

Benati, Rogerio Bodini ^[1] ; Costa, Tassia Rafaela ^[1] ; Cacemiro, Maira da Costa ^[1] ; Sampaio, Suely Vilela ^[1] ; de Castro, Fabiola Attie ^[1] ; Burin, Sandra Mara ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Venomous Animals and Toxins including Tropical Diseases; v. 24, DEC 20 2018.
• Citações Web of Science: 2

Resumo

Abstract Background: Chronic myeloid leukemia (CML) is a BCR-ABL1+ myeloproliferative neoplasm marked by increased myeloproliferation and presence of leukemic cells resistant to apoptosis. The current first-line therapy for CML is administration of the tyrosine kinase inhibitors imatinib mesylate, dasatinib or nilotinib. Although effective to treat CML, some patients have become resistant to this therapy, leading to disease progression and death. Thus, the discovery of new compounds to improve CML therapy is still challenging. Here we addressed whether MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, affects the viability of imatinib mesylate-resistant Bcr-Abl+ cell lines. Methods: We examined the cytotoxic and pro-apoptotic effect of MjTX-I in K562-S and K562-R Bcr-Abl+ cells and in the non-tumor HEK-293 cell line and peripheral blood mononuclear cells, using the 3-(4,5-dimethylthiazol-2-yl) −2,5-diphenyltetrazolium bromide and the hypotonic fluorescent solution methods, associated with detection of caspases 3, 8, and 9 activation and poly (ADP-ribose) polymerase (PARP) cleavage. We also analyzed the MjTX-I potential to modulate the expression of apoptosis-related genes in K562-S and K562-R cells. Results: MjTX-I decreased the viability of K562-S and K562-R cells by 60 to 65%, without affecting the viability of the non-tumor cells, i.e. it exerted selective cytotoxicity towards Bcr-Abl+ cell lines. In leukemic cell lines, the toxin induced apoptosis, activated caspases 3, 8, and 9, cleaved PARP, downregulated expression of the anti-apoptotic gene BCL-2, and upregulated expression of the pro-apoptotic gene BAD. Conclusion: The antitumor effect of MjTX-I is associated with its potential to induce apoptosis and cytotoxicity in Bcr-Abl positive cell lines sensitive and resistant to imatinib mesylate, indicating that MjTX-I is a promising candidate drug to upgrade the CML therapy. (AU)

• Processo FAPESP: 15/00740-0 - Avaliação do potencial terapêutico de L-aminoácido oxidases isoladas de peçonhas de serpentes como antitumoral: estudos de genotoxicidade e expressão gênica
• Beneficiário: Tássia Rafaella Costa
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/25637-7 - Modulação epigenética da maquinaria apoptótica em células Bcr-Abl positivas pelas toxinas BmooLAAO-I e MjTX-I
• Beneficiário: Sandra Mara Burin de Menezes
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 11/23236-4 - Toxinas animais nativas e recombinantes: análise funcional, estrutural e molecular
• Beneficiário: Suely Vilela
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 14/04234-9 - Expressão das moléculas da via HIPPO/LATS em neoplasias mieloproliferativas crônicas
• Beneficiário: Maira da Costa Cacemiro
• Modalidade de apoio: Bolsas no Brasil - Doutorado