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The mechanism of synergistic effects of arsenic trioxide and rapamycin in acute myeloid leukemia cell lines lacking typical t(15;17) translocation

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Abstract

Arsenic trioxide (ATO) has potent clinical activity in the treatment of patients with acute promyelocytic leukemia (APL), but is much less efficacious in acute myeloid leukemia (AML) lacking t(15;17) translocation. Recent studies have indicated that the addition of mammalian target of rapamycin (mTOR) inhibitors may increase the sensitivity of malignant cells to ATO. The aim of the present study was to test for possible synergistic effects of ATO and rapamycin at therapeutically achievable doses in non-APL AML cells. In HL-60 and U937 cell lines, the inhibitory effects of low concentrations of ATO and rapamycin were synergistic and more pronounced in U937 cells. The combination of drugs increased apoptosis in HL-60 cells and increased the percentage of cells in G0/G1 phase in both cell lines. In U937 cells, rapamycin alone increased the activity of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and the addition of ATO decreased the level of phosphorylated ERK, Ser473 phosphorylated Akt and anti-apoptotic Mcl-1 protein. Primary AML cells show high sensitivity to growth-inhibitory effects of rapamycin alone or in combination with ATO. The results of the present study reveal the mechanism of the synergistic effects of two drugs at therapeutically achievable doses in non-APL AML cells.

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Acknowledgments

We thank Dunja Tankovic for valuable technical help and assistance and Gabriel Borden for editing the manuscript. This work was supported by the Ministry of Science, Education and Sport of the Republic of Croatia, Grants No. 108-1081347-1448 (to D. V.) and 108-1081347-0173 (to H. B.), and University of Zagreb Research Grant No. 2013-ZIUD-02 (to D.V.).

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Authors and Affiliations

  1. Department of Physiology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 3, POB 978, 10 000, Zagreb, Croatia

    Vilma Dembitz, Hrvoje Lalic, Hrvoje Banfic & Dora Visnjic

  2. Department of Hematology, University Hospital Centre Zagreb, Kispaticeva 12, 10 000, Zagreb, Croatia

    Alen Ostojic & Radovan Vrhovac

  3. Department of Internal Medicine, School of Medicine, University of Zagreb, Salata 3, 10 000, Zagreb, Croatia

    Radovan Vrhovac

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  1. Vilma Dembitz
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  2. Hrvoje Lalic
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  6. Dora Visnjic
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Correspondence to Dora Visnjic.

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Dembitz, V., Lalic, H., Ostojic, A. et al. The mechanism of synergistic effects of arsenic trioxide and rapamycin in acute myeloid leukemia cell lines lacking typical t(15;17) translocation. Int J Hematol 102, 12–24 (2015). https://doi.org/10.1007/s12185-015-1776-2

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  • DOI: https://doi.org/10.1007/s12185-015-1776-2

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