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

Autor(es)

Chura-Chambi, R. M. ^[1] ; Bellini, M. H. ^[1] ; Jacysyn, J. F. ^[2] ; Andrade, L. N. ^[3] ; Medina, L. P. ^[4] ; Prieto-da-Silva, A. R. B. ^[5] ; Amarante-Mendes, G. P. ^[4] ; Morganti, L. ^[1]

Afiliação do(s) autor(es)

^[1] IPEN, CNEN SP, Ctr Biotechnol, BR-05508000 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, LIM62, Sao Paulo - Brazil

^[3] Inst Canc Estado Sao Paulo, Ctr Invest Translac Oncol, Dept Radiol & Oncol, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Inst Ciencias Biomed, Dept Imunol, BR-05508 Sao Paulo - Brazil

^[5] Inst Butantan, Lab Imunopatol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CELL DEATH & DISEASE; v. 5, AUG 2014.
• Citações Web of Science: 3

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. (AU)

• Processo FAPESP: 03/07949-4 - Estudo de atividade antiangiogenica de proteinas de fusao endostatina-peptideos com atividade apoptotica.
• Beneficiário: Ligia Ely Morganti Ferreira Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular