Cytotoxic and pro-apoptotic action of MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, towards leukemic cells
AUTOR(ES)
Benati, Rogério Bodini
FONTE
J. Venom. Anim. Toxins incl. Trop. Dis
DATA DE PUBLICAÇÃO
24/01/2019
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.
Documentos Relacionados
- Cytotoxic and inflammatory potential of a phospholipase A2 from Bothrops jararaca snake venom
- Physicoquemical and biologic characterization of phospholipase A2 isolated from Bothrops moojeni venom
- Functional and Structural Characterization of an Acidic Toxic Phospholipase A2 from Bothrops moojeni Snake Venom.
- Biological characterization of a myotoxin phosphoplipase A2 homologue purified from the venom of the snake Bothrops moojeni
- Functional and structural characterization of phospholipases A² isolated from Bothrops asper snake venom in Panamá