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Inhibition of Forkhead box protein M1 by thiostrepton increases chemosensitivity to doxorubicin in T-cell acute lymphoblastic leukemia

  • Authors:
    • Jian‑Yong Wang
    • Xiu‑Hong Jia
    • Hai‑Yan Xing
    • You‑Jie Li
    • Wen‑Wen Fan
    • Na Li
    • Shu‑Yang Xie

  • View Affiliations

  • Published online on: March 11, 2015     https://doi.org/10.3892/mmr.2015.3469
  • Pages: 1457-1464
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood malignancy, deriving from T-cell progenitors in the thymus, and comprises 10‑15% of pediatric and 25% of adult primary ALL cases. Despite advances, 20% of pediatric and the majority of adult patients with T-ALL succumb to mortality from resistant or relapsed disease, and the survival rate for patients with resistant or relapsed T-ALL remains poor. Alterations in the expression of Forkhead box protein M1 (FoxM1) have been detected in several types of cancer, and the inhibition of FoxM1 has been investigated as therapeutic strategy in cancer. The present study investigated the effects of the inhibition of FoxM1 by thiostrepton in human T-ALL Jurkat cells. The cells were treated with different concentrations of thiostrepton, either alone or in combination with doxorubicin. Cell viability was measured using CCK-8 assays and the cell cycle distribution, apoptosis and cell-associated mean fluorescence intensity of intracellular doxorubicin were assessed using flow cytometric analysis. The mRNA and protein expression levels were detected by reverse transcription‑quantitative polymerase chain reaction and western blot analyses. The inhibition of FoxM1 by thiostrepton significantly decreased the proliferation of the Jurkat cells proliferation in a time- and dose-dependent manner. Cell arrest at the G2/M phase, and apoptosis was significantly increased in the thiostrepton-treated Jurkat cells. Thiostrepton reduced the half maximal inhibitory concentration of doxorubicin in the Jurkat cells, and significantly enhanced the cytotoxicity of doxorubicin within the Jurkat cells by enhancing doxorubicin-induced apoptosis and increasing the accumulation of intracellular doxorubicin. Furthermore, the inhibition of FoxM1 by thiostrepton enhanced doxorubicin-induced apoptosis, possibly through a caspase-3-dependent pathway, and increased the accumuation of intracellular doxorubicin, possibly through downregulating the expression of glutathione S-transferase pi. Collectively, the results of the present study suggested that targeting FoxM1 with thiostrepton resulted in potent antileukemia activity and chemosensitizing effects in human T-ALL Jurkat cells.
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July-2015
Volume 12 Issue 1

Print ISSN: 1791-2997
Online ISSN:1791-3004

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  • Impact Factor: 3.4
  • Ranked Medicine Research and Experimental
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  • CiteScore: 7.6
  • CiteScore Rank: Q1: #82/347 Biochemistry, Genetics and Molecular Biology
  • Source Normalized Impact per Paper (SNIP): 0.647
  • SCImago Journal Rank (SJR): 0.781
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Spandidos Publications style
Wang JY, Jia XH, Xing HY, Li YJ, Fan WW, Li N and Xie SY: Inhibition of Forkhead box protein M1 by thiostrepton increases chemosensitivity to doxorubicin in T-cell acute lymphoblastic leukemia. Mol Med Rep 12: 1457-1464, 2015.
APA
Wang, J., Jia, X., Xing, H., Li, Y., Fan, W., Li, N., & Xie, S. (2015). Inhibition of Forkhead box protein M1 by thiostrepton increases chemosensitivity to doxorubicin in T-cell acute lymphoblastic leukemia. Molecular Medicine Reports, 12, 1457-1464. https://doi.org/10.3892/mmr.2015.3469
MLA
Wang, J., Jia, X., Xing, H., Li, Y., Fan, W., Li, N., Xie, S."Inhibition of Forkhead box protein M1 by thiostrepton increases chemosensitivity to doxorubicin in T-cell acute lymphoblastic leukemia". Molecular Medicine Reports 12.1 (2015): 1457-1464.
Chicago
Wang, J., Jia, X., Xing, H., Li, Y., Fan, W., Li, N., Xie, S."Inhibition of Forkhead box protein M1 by thiostrepton increases chemosensitivity to doxorubicin in T-cell acute lymphoblastic leukemia". Molecular Medicine Reports 12, no. 1 (2015): 1457-1464. https://doi.org/10.3892/mmr.2015.3469