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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 13
[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
Total Affiliations: 4
Document type: Journal article
Web of Science Citations: 5

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)

FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
Grantee:Dimas Tadeu Covas
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC