Improving the therapeutic potential of endostatin by fusing it with the BAX BH3 death domain

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art_CHURA-CHAMBI_Improving_the_therapeutic_potential_of_endostatin_by_fusing_2014.PDF (2.28 MB)
Citações na Scopus
3
Tipo de produção
article
Data de publicação
2014
DOI
Scopus
Web of Science
Título da Revista
ISSN da Revista
Título do Volume
Editora
NATURE PUBLISHING GROUP
Autores
CHURA-CHAMBI, R. M.
BELLINI, M. H.
MEDINA, L. P.
PRIETO-DA-SILVA, A. R. B.
AMARANTE-MENDES, G. P.
MORGANTI, L.
Citação
CELL DEATH & DISEASE, v.5, article ID e1371, 10p, 2014
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Endostatin (ES) inhibits angiogenesis, reducing tumor growth in animal models. However, it has low therapeutic effect in human clinical trials. BAX is a member of the BCL-2 family of proteins; its proapoptotic (BH3) domain interacts with other members of the family in the cytoplasm, to induce apoptosis. Here, we fused the BAX BH3 domain with murine ES, to enhance ES potency. Endothelial cells specifically internalize the fusion protein ES-BAX. The presence of the BAX domain enhances endothelial cell death by apoptosis by 1.8-fold and diminishes microvessel outgrowth in the rat aortic ring assay by 6.5-fold. Daily injections of 15 mu g of ES-BAX/g in tumor-bearing mice reduce tumor weight by 86.9% as compared with ES-treated animals. Co-immunoprecipitation assays confirmed that ES-BAX interacts with members of the BCL-2 family. Also, ES interacts with BCL-2, BCL-XL, and BAK in endothelial cell lysates, suggesting a potential new mechanism for the apoptosis induction by ES. The superiority of the ES-BAX antiangiogenic effect indicates that this fusion protein could be a promising therapeutic alternative to treat cancer.
Palavras-chave
URI
https://observatorio.fm.usp.br/handle/OPI/8705
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Coleções
Artigos e Materiais de Revistas Científicas - HC/ICESP
Artigos e Materiais de Revistas Científicas - LIM/62
Artigos e Materiais de Revistas Científicas - ODS/03