title: The pterocarpanquinone LQB-118 induces apoptosis in acute myeloid leukemia cells of distinct molecular subtypes and targets FoxO3a and FoxM1 transcription factors.
abstract: Acute myeloid leukemia (AML) patients' outcome is usually poor, mainly because of drug resistance phenotype. The identification of new drugs able to overcome mechanisms of chemoresistance is essential. The pterocarpanquinone LQB-118 compound has been shown to have a potent cytotoxic activity in myeloid leukemia cell lines and patient cells. Our aim was to investigate if LQB-118 is able to target FoxO3a and FoxM1 signaling pathways while sensitizing AML cell lines. LQB-118 induced apoptosis in both AML cell lines HL60 (M3 FAB subtype) and U937 (M4/M5 FAB subtype). Cell death occurred independently of alterations in cell cycle distribution. In vivo administration revealed that LQB-118 was not cytotoxic to normal bone marrow-derived cells isolated from mice. LQB-118 induced FoxO3a nuclear translocation and upregulation of its direct transcriptional target Bim, in HL60 cells. However, LQB-118 induced FoxO3a nuclear exclusion, followed by Bim downregulation, in U937 cells. Concomitantly, LQB-118 exposure reduced FoxM1 and Survivin expression in U937 cells, but this effect was more subtle in HL60 cells. Taken together, our data suggest that LQB-118 has a selective and potent antitumor activity against AML cells with distinct molecular subtypes, and it involves differential modulation of the signaling pathways associated with FoxO3a and FoxM1 transcription factors.
authors.affiliation: Laboratory of Cellular and Molecular Hemato-Oncology, Program of Molecular Hemato-Oncology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Nestal de Moraes
authors.affiliation: Laboratory of Cellular and Molecular Hemato-Oncology, Program of Molecular Hemato-Oncology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil.
authors.forename: Carolina Pereira
authors.initials: CP
authors.lastname: Castro
authors.affiliation: Laboratory of Bioorganic Chemistry, Research Nucleous of Natural Products, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Eduardo Jesus
authors.initials: EJ
authors.lastname: Salustiano
authors.affiliation: Laboratory of Tumor Immunology, Leopoldo de Meis Medical Biochemistry Institute (IBqM-UFRJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Matheus Lourenço
authors.initials: ML
authors.lastname: Dumas
authors.affiliation: Laboratory of Cellular and Molecular Hemato-Oncology, Program of Molecular Hemato-Oncology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Costas
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Eric Wing-Fai
authors.initials: EW
authors.lastname: Lam
authors.affiliation: Laboratory of Bioorganic Chemistry, Research Nucleous of Natural Products, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Paulo Roberto Ribeiro
authors.initials: PR
authors.lastname: Costa
authors.affiliation: Laboratory of Cellular and Molecular Hemato-Oncology, Program of Molecular Hemato-Oncology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil.
authors.forename: Raquel Ciuvalschi
authors.initials: RC
authors.lastname: Maia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D000072278:Forkhead Box Protein M1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009285:Naphthoquinones / Q000008:administration & dosage*; D036343:Pterocarpans / Q000008:administration & dosage*
chemical_list: C107585:FOXM1 protein, human; C499517:FOXO3 protein, human; D000072278:Forkhead Box Protein M1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C569361:LQB 118; D009285:Naphthoquinones; D036343:Pterocarpans