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The pterocarpanquinone LQB-118 induces apoptosis in acute myeloid leukemia cells of distinct molecular subtypes and targets FoxO3a and FoxM1 transcription factors.

Authors
  • Nestal de Moraes, Gabriela1
  • Castro, Carolina Pereira1
  • Eduardo Salustiano2, 3
  • Dumas, Matheus Lourenço4
  • Costas, Fernanda1
  • Lam, Eric Wing-Fai5
  • Costa, Paulo Roberto Ribeiro6
  • Maia, Raquel Ciuvalschi1
Type
Published Article
Journal
International Journal of Oncology
Publisher
Spandidos Publications
Publication Date
Nov 03, 2014
Accepted Date
Jul 02, 2014
Volume
45
Issue
5
Pages
1949–1958
Identifiers
DOI: 10.3892/ijo.2014.2615
PMID: 25174716
Source
Medline
Keywords
License
Unknown

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.

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