Halofuginone inhibits phosphorylation of SMAD-2 reducing angiogenesis and leukemia burden in an acute promyelocytic leukemia mouse model

Autor(es):Mostrar menos -

Assis, Patricia A. ^[1] ; De Figueiredo-Pontes, Lorena L. ^[1] ; Lima, Ana Silvia G. ^[1] ; Leao, Vitor ^[1] ; Candido, Larissa A. ^[1] ; Pintao, Carolina T. ^[1] ; Garcia, Aglair B. ^[1] ; Saggioro, Fabiano P. ^[2] ; Panepucci, Rodrigo A. ^[1] ; Chahud, Fernando ^[2] ; Nagler, Arnon ^{[3, 4]} ; Falcao, Roberto P. ^[1] ; Rego, Eduardo M. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Med Sch Ribeirao Preto, Dept Internal Med, Div Hematol & Oncol, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Med Sch Ribeirao Preto, Dept Pathol, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Tel Aviv Univ, Chaim Sheba Med Ctr, Div Hematol, IL-6997801 Tel Hashomer - Israel

^[4] Tel Aviv Univ, Chaim Sheba Med Ctr, Cord Blood Bank, IL-6997801 Tel Hashomer - Israel

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH; v. 34, JUN 23 2015.
• Citações Web of Science: 5

Resumo

Background: Halofuginone (HF) is a low-molecular-weight alkaloid that has been demonstrated to interfere with Metalloproteinase-2 (MMP-2) and Tumor Growth Factor-beta (TGF-beta) function and, to present antiangiogenic, antiproliferative and proapoptotic properties in several solid tumor models. Based on the fact that high levels of Vascular Endothelial Growth Factor (VEGF) and increased angiogenesis have been described in acute myeloid leukemia and associated with disease progression, we studied the in vivo effects of HF using an Acute Promyelocytic Leukemia (APL) mouse model. Methods: NOD/SCID mice were transplanted with leukemic cells from hCG-PML/RARA transgenic mice (TM) and treated with HF 150 mu g/kg/day for 21 days. The leukemic infiltration and the percentage of VEGF+ cells were evaluated by morphology and flow cytometry. The effect of HF on the gene expression of several pro-and antiangiogenic factors, phosphorylation of SMAD2 and VEGF secretion was assessed in vitro using NB4 and HUVEC cells. Results: HF treatment resulted in hematological remission with decreased accumulation of immature cell and lower amounts of VEGF in BM of leukemic mice. In vitro, HF modulated gene expression of several pro-and antiangiogenic factors, reduced VEGF secretion and phosphorylation of SMAD2, blocking TGF-beta-signaling. Conclusion: Taken together, our results demonstrate that HF inhibits SMAD2 signaling and reduces leukemia growth and angiogenesis. (AU)

• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 08/52634-5 - Analise do efeito antileucemico da halofuginona no modelo transgenico de leucemia promielocitica aguda.
• Beneficiário: Patricia Aparecida de Assis
• Modalidade de apoio: Bolsas no Brasil - Mestrado