The pterocarpanquinone LQB‑118 compound induces apoptosis of cytarabine‑resistant acute myeloid leukemia cells

Hancio,Thaís; Mazzoccoli,Luciano; Guimarães,Gustavo; Robaina,Marcela; Mendonça,Bruna  Dos Santos; Nestal De Moraes,Gabriela; Monte‑Mor,Barbara  Da Costa Reis; Mayumi Gutiyama,Luciana; De Carvalho,Luíze  Otero; Netto,Chaquip Daher; Costa,Paulo R.R.; De Faria,Fernanda Costas Casal; Maia,Raquel Ciuvalschi

doi:10.3892/ijo.2021.5204

The pterocarpanquinone LQB‑118 compound induces apoptosis of cytarabine‑resistant acute myeloid leukemia cells

Authors:
- Thaís Hancio
- Luciano Mazzoccoli
- Gustavo Guimarães
- Marcela Robaina
- Bruna Dos Santos Mendonça
- Gabriela Nestal De Moraes
- Barbara Da Costa Reis Monte‑Mor
- Luciana Mayumi Gutiyama
- Luíze Otero De Carvalho
- Chaquip Daher Netto
- Paulo R.R. Costa
- Fernanda Costas Casal De Faria
- Raquel Ciuvalschi Maia
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Affiliations: Laboratory of Cellular and Molecular Hemato‑Oncology, Program of Molecular Hemato‑Oncology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ 20230‑130, Brazil, Laboratory of Molecular Biology, Bone Marrow Transplant Center (CEMO), Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ 20230‑130, Brazil, Stem Cell Laboratory, Bone Marrow Transplant Center (CEMO), Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ 20230‑130, Brazil, Chemistry Laboratory, Federal University of Rio de Janeiro (UFRJ), Macaé Campus, Rio de Janeiro, RJ 27930‑560, Brazil, Bioorganic Chemistry Laboratory, Natural Products Research Institute (IPPN), Rio de Janeiro Federal University (UFRJ), Rio de Janeiro, RJ 21941‑599, Brazil
Published online on: March 30, 2021 https://doi.org/10.3892/ijo.2021.5204
Article Number: 24

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Abstract

Acute myeloid leukemia (AML) is a complex hematological disorder characterized by blockage of differentiation and high proliferation rates of myeloid progenitors. Anthracycline and cytarabine‑based therapy has remained the standard treatment for AML over the last four decades. Although this treatment strategy has increased survival rates, patients often develop resistance to these drugs. Despite efforts to understand the mechanisms underlying cytarabine resistance, there have been few advances in the field. The present study developed an in vitro AML cell line model resistant to cytarabine (HL‑60R), and identified chromosomal aberrations by karyotype evaluation and potential molecular mechanisms underlying chemoresistance. Cytarabine decreased cell viability, as determined by MTT assay, and induced cell death and cell cycle arrest in the parental HL‑60 cell line, as revealed by Annexin V/propidium iodide (PI) staining and PI DNA incorporation, respectively, whereas no change was observed in the HL‑60R cell line. In addition, the HL‑60R cell line exhibited a higher tumorigenic capacity in vivo compared with the parental cell line. Notably, no reduction in tumor volume was detected in mice treated with cytarabine and inoculated with HL‑60R cells. In addition, western blotting revealed that the protein expression levels of Bcl‑2, X‑linked inhibitor of apoptosis protein (XIAP) and c‑Myc were upregulated in HL‑60R cells compared with those in HL‑60 cells, along with predominant nuclear localization of the p50 and p65 subunits of NF‑κB in HL‑60R cells. Furthermore, the antitumor effect of LQB‑118 pterocarpanquinone was investigated; this compound induced apoptosis, a reduction in cell viability and a decrease in XIAP expression in cytarabine‑resistant cells. Taken together, these data indicated that acquired cytarabine resistance in AML was a multifactorial process, involving chromosomal aberrations, and differential expression of apoptosis and cell proliferation signaling pathways. Furthermore, LQB‑118 could be a potential alternative therapeutic approach to treat cytarabine‑resistant leukemia cells.

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