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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 6
[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, Ribeirao Preto, SP - Brazil
Total Affiliations: 1
Document type: Journal article
Source: Journal of Venomous Animals and Toxins including Tropical Diseases; v. 24, DEC 20 2018.
Web of Science Citations: 0

BackgroundChronic 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 A(2) isolated from Bothrops moojeni snake venom, affects the viability of imatinib mesylate-resistant Bcr-Abl(+) cell lines.MethodsWe 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.ResultsMjTX-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.ConclusionThe 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)

FAPESP's process: 15/25637-7 - Epigenetic modulation of apoptotic machinery in Bcr-Abl positive cells by BmooLAAO-I and MjTX-I toxins
Grantee:Sandra Mara Burin de Menezes
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 15/00740-0 - Therapeutic potential evaluation of L-amino acid oxidases isolated from snake venoms as antitumor: genotoxicity and gene expression studies
Grantee:Tássia Rafaella Costa
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 11/23236-4 - Native and recombinant animal toxins: functional, structural and molecular analysis
Grantee:Suely Vilela
Support type: Research Projects - Thematic Grants
FAPESP's process: 14/04234-9 - Expression of molecules of HIPPO/LATS pathway in chronic neoplasms myeloproliferative
Grantee:Maira da Costa Cacemiro
Support type: Scholarships in Brazil - Doctorate