Halofuginone Has Anti-Proliferative Effects in Acute Promyelocytic Leukemia by Modulating the Transforming Growth Factor Beta Signaling Pathway

Autor(es):Mostrar menos -

de Figueiredo-Pontes, Lorena L. ^[1] ; Assis, Patricia A. ^[1] ; Santana-Lemos, Barbara A. A. ^[1] ; Jacomo, Rafael H. ^[2] ; Lima, Ana Silvia G. ^[1] ; Garcia, Aglair B. ^[1] ; Thome, Carolina H. ^[1] ; Araujo, Amelia G. ^[1] ; Panepucci, Rodrigo A. ^[1] ; Zago, Marco A. ^[1] ; 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, Div Hematol, Dept Internal Med, Sao Paulo - Brazil

^[2] Univ Brasilia, Div Hematol, Dept Internal Med, Sch Med, Brasilia, DF - Brazil

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

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

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 6, n. 10, p. e26713, 2011.
• Citações Web of Science: 20

Resumo

Promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) expression in acute promyelocytic leukemia (APL) impairs transforming growth factor beta (TGF beta) signaling, leading to cell growth advantage. Halofuginone (HF), a low-molecular-weight alkaloid that modulates TGFb signaling, was used to treat APL cell lines and non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice subjected to transplantation with leukemic cells from human chorionic gonadotrophin-PML-RAR alpha transgenic mice (TG). Cell cycle analysis using incorporated bromodeoxyuridine and 7-amino-actinomycin D showed that, in NB4 and NB4-R2 APL cell lines, HF inhibited cellular proliferation (P<0.001) and induced apoptosis (P = 0.002) after a 24-hour incubation. Addition of TGFb revealed that NB4 cells were resistant to its growth-suppressive effects and that HF induced these effects in the presence or absence of the cytokine. Cell growth inhibition was associated with up-regulation of TGFb target genes involved in cell cycle regulation (TGFB, TGFBRI, SMAD3, p15, and p21) and downregulation of MYC. Additionally, TGFb protein levels were decreased in leukemic TG animals and HF in vivo could restore TGFb values to normal. To test the in vivo anti-leukemic activity of HF, we transplanted NOD/SCID mice with TG leukemic cells and treated them with HF for 21 days. HF induced partial hematological remission in the peripheral blood, bone marrow, and spleen. Together, these results suggest that HF has anti-proliferative and anti-leukemic effects by reversing the TGFb blockade in APL. Since loss of the TGFb response in leukemic cells may be an important second oncogenic hit, modulation of TGFb signaling may be of therapeutic interest. (AU)

• Processo FAPESP: 98/14247-6 - Center for Research on Cell-Based Therapy
• Beneficiário: Marco Antonio Zago
• 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
• Processo FAPESP: 02/11086-9 - Criação e análise de um modelo transgênico de leucemia megacarioblástica aguda da infância associada a t(1;22) / OTT-MAL
• Beneficiário: Lorena Lôbo de Figueiredo Pontes
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto