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

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, d...

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Main Authors: Rogério Bodini Benati, Tássia Rafaela Costa, Maira da Costa Cacemiro, Suely Vilela Sampaio, Fabíola Attié de Castro, Sandra Mara Burin
Format: Article
Language:English
Published: SciELO 2018-12-01
Series:Journal of Venomous Animals and Toxins including Tropical Diseases
Subjects:
Online Access:http://link.springer.com/article/10.1186/s40409-018-0180-9
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spelling doaj-a1b4550a7ea3431c9be9d4c26928a1952020-11-24T23:54:50ZengSciELOJournal of Venomous Animals and Toxins including Tropical Diseases1678-91992018-12-012411910.1186/s40409-018-0180-9Cytotoxic and pro-apoptotic action of MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, towards leukemic cellsRogério Bodini Benati0Tássia Rafaela Costa1Maira da Costa Cacemiro2Suely Vilela Sampaio3Fabíola Attié de Castro4Sandra Mara Burin5Departamento de Análises Clínicas, Toxicológicas e Bromatológicas. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloDepartamento de Análises Clínicas, Toxicológicas e Bromatológicas. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloDepartamento de Análises Clínicas, Toxicológicas e Bromatológicas. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloDepartamento de Análises Clínicas, Toxicológicas e Bromatológicas. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloDepartamento de Análises Clínicas, Toxicológicas e Bromatológicas. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloDepartamento de Análises Clínicas, Toxicológicas e Bromatológicas. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloAbstract 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.http://link.springer.com/article/10.1186/s40409-018-0180-9Chronic myeloid leukemiaBcr-AblPhospholipase A2MjTX-IBothrops moojeniApoptosis
collection DOAJ
language English
format Article
sources DOAJ
author Rogério Bodini Benati
Tássia Rafaela Costa
Maira da Costa Cacemiro
Suely Vilela Sampaio
Fabíola Attié de Castro
Sandra Mara Burin
spellingShingle Rogério Bodini Benati
Tássia Rafaela Costa
Maira da Costa Cacemiro
Suely Vilela Sampaio
Fabíola Attié de Castro
Sandra Mara Burin
Cytotoxic and pro-apoptotic action of MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, towards leukemic cells
Journal of Venomous Animals and Toxins including Tropical Diseases
Chronic myeloid leukemia
Bcr-Abl
Phospholipase A2
MjTX-I
Bothrops moojeni
Apoptosis
author_facet Rogério Bodini Benati
Tássia Rafaela Costa
Maira da Costa Cacemiro
Suely Vilela Sampaio
Fabíola Attié de Castro
Sandra Mara Burin
author_sort Rogério Bodini Benati
title Cytotoxic and pro-apoptotic action of MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, towards leukemic cells
title_short Cytotoxic and pro-apoptotic action of MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, towards leukemic cells
title_full Cytotoxic and pro-apoptotic action of MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, towards leukemic cells
title_fullStr Cytotoxic and pro-apoptotic action of MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, towards leukemic cells
title_full_unstemmed Cytotoxic and pro-apoptotic action of MjTX-I, a phospholipase A2 isolated from Bothrops moojeni snake venom, towards leukemic cells
title_sort cytotoxic and pro-apoptotic action of mjtx-i, a phospholipase a2 isolated from bothrops moojeni snake venom, towards leukemic cells
publisher SciELO
series Journal of Venomous Animals and Toxins including Tropical Diseases
issn 1678-9199
publishDate 2018-12-01
description 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.
topic Chronic myeloid leukemia
Bcr-Abl
Phospholipase A2
MjTX-I
Bothrops moojeni
Apoptosis
url http://link.springer.com/article/10.1186/s40409-018-0180-9
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