title: Halofuginone has anti-proliferative effects in acute promyelocytic leukemia by modulating the transforming growth factor beta signaling pathway.
abstract: Promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) expression in acute promyelocytic leukemia (APL) impairs transforming growth factor beta (TGFβ) signaling, leading to cell growth advantage. Halofuginone (HF), a low-molecular-weight alkaloid that modulates TGFβ 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-RARα 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 TGFβ 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 TGFβ target genes involved in cell cycle regulation (TGFB, TGFBRI, SMAD3, p15, and p21) and down-regulation of MYC. Additionally, TGFβ protein levels were decreased in leukemic TG animals and HF in vivo could restore TGFβ 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 TGFβ blockade in APL. Since loss of the TGFβ response in leukemic cells may be an important second oncogenic hit, modulation of TGFβ signaling may be of therapeutic interest.
authors: Hematology Division of the Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors: Lorena L
authors: LL
authors: de Figueiredo-Pontes
authors: Patricia A
authors: PA
authors: Assis
authors: Bárbara A A
authors: BA
authors: Santana-Lemos
authors: Rafael H
authors: RH
authors: Jácomo
authors: Ana Sílvia G
authors: AS
authors: Lima
authors: Aglair B
authors: AB
authors: Garcia
authors: Carolina H
authors: CH
authors: Thomé
authors: Amélia G
authors: AG
authors: Araújo
authors: Rodrigo A
authors: RA
authors: Panepucci
authors: Marco A
authors: MA
authors: Zago
authors: Arnon
authors: A
authors: Nagler
authors: Roberto P
authors: RP
authors: Falcão
authors: Eduardo M
authors: EM
authors: Rego
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D052999:Quinazolinones / Q000494:pharmacology*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D052999:Quinazolinones; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C010176:halofuginone