Epigenetic modulation of apoptotic machinery in Bcr-Abl positive cells by BmooLAAO-I and MjTX-I toxins

• Grant number: 15/25637-7
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): February 01, 2016
• Effective date (End): September 30, 2018
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Suely Vilela
• Grantee: Sandra Mara Burin de Menezes
• Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 11/23236-4 - Native and recombinant animal toxins: functional, structural and molecular analysis, AP.TEM

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm cytogenetically characterized by the presence of the Philadelfia (Ph) chromosome and molecularly by the appearance of the BCR-ABL1 neogene that encodes the Bcr-Abl oncoprotein with constitutive tyrosine kinase (TK) activity. Bcr-Abl expression promotes myeloproliferation, decreased hematopoietic cell adhesion to the medullary stroma, and resistance to apoptosis through transformation of the normal hematopoietic cell into leukemic. The treatment of CML can be performed through different therapeutic modalities, including imatinib mesylate (MI), a Bcr-Abl tyrosine kinase inhibitor. Although IM is efficient, patients in advanced stages of the disease and some in the chronic phase are resistant to this therapy, mainly due to the presence of mutations at the Bcr-Abl catalytic site, such as the T315I mutation. In this context, it is necessary to describe new and more efficient therapies for CML. The objective of the present project is to investigate the effect of the toxins L-amino acid oxidase (LAAO) and phospholipase A2 (PLA2) isolated from Bothrops moojeni - BmooLAA-I and MjTX-I (myotoxin PLA2-Lys49) respectively - in the methylation profile of the regulatory genes of apoptosis and in the expression of microRNAs (miRNAs) that target genes that regulate apoptosis. In addition, simultaneous expression of proteins involved in apoptosis and some cell signaling pathways such as STAT-5, MAPK / ERK and PI3K / AKT / mTOR will be evaluated. Studies have shown that LAAOs and PLA2s isolated from snakes can induce various effects of therapeutic interest such as antimicrobial, antiparasitic, antiviral and inducer of cellular apoptosis. The study will be performed on mononuclear cells (MNC) of patients with CML and on the resistant and sensitive MI HL-60 and Bcr-Abl positive cell lines (HL-60.Bcr-Abl, K562-S and K562-R). The data obtained during the development of this project may contribute to the description of new substances for the treatment of CML and substances with potential epigenetic and protein modulators. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BENATI, ROGERIO BODINI; COSTA, TASSIA RAFAELA; CACEMIRO, MAIRA DA COSTA; SAMPAIO, SUELY VILELA; DE CASTRO, FABIOLA ATTIE; BURIN, SANDRA MARA. 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, v. 24, DEC 20 2018. Web of Science Citations: 2.

BURIN, SANDRA M.; MENALDO, DANILO L.; SAMPAIO, SUELY V.; FRANTZ, FABIANI G.; CASTRO, FABIOLA A. An overview of the immune modulating effects of enzymatic toxins from snake venoms. International Journal of Biological Macromolecules, v. 109, p. 664-671, APR 2018. Web of Science Citations: 2.

CARONE, SANTE E. I.; COSTA, TASSIA R.; BURIN, SANDRA M.; CINTRA, ADELIA C. O.; ZOCCAL, KARINA F.; BIANCHINI, FRANCINE J.; TUCCI, LUIZ F. F.; FRANCO, JOAO J.; TORQUETI, MARIA R.; FACCIOLI, LUCIA H.; DE ALBUQUERQUE, SERGIO; DE CASTRO, FABIOLA A.; SAMPAIO, SUELY V. A new L-amino acid oxidase from Bothrops jararacussu snake venom: Isolation, partial characterization, and assessment of pro-apoptotic and antiprotozoal activities. International Journal of Biological Macromolecules, v. 103, p. 25-35, OCT 2017. Web of Science Citations: 13.

CACEMIRO, MAIRA DA COSTA; BERZOTI-COELHO, MARIA GABRIELA; COMINAL, JUCARA GASTALDI; BURIN, SANDRA MARA; DE CASTRO, FABIOLA ATTIE. Hippo pathway deregulation: implications in the pathogenesis of haematological malignancies. Journal of Clinical Pathology, v. 70, n. 1, p. 9-14, JAN 2017. Web of Science Citations: 0.

BURIN, SANDRA MARA; BERZOTI-COELHO, MARIA GABRIELA; COMINAL, JUCARA GASTALDI; AMBROSIO, LUCIANA; TORQUETI, MARIA REGINA; SAMPAIO, SUELY VILELA; DE CASTRO, FABIOLA ATTIE. The L-amino acid oxidase from Calloselasma rhodostoma snake venom modulates apoptomiRs expression in Bcr-Abl-positive cell lines. Toxicon, v. 120, p. 9-14, SEP 15 2016. Web of Science Citations: 10.