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Combined Inhibition of PI3K and mTOR Exerts Synergistic Antiproliferative Effect, but Diminishes Differentiative Properties of Rapamycin in Acute Myeloid Leukemia Cells

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Pathology & Oncology Research

Abstract

A novel strategy has been suggested to enhance rapamycin-based cancer therapy through combining mammalian target of rapamycin (mTOR)-inhibitors with an inhibitor of the phosphatydilinositol 3-kinase PI3K/Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. However, recent study demonstrated the potentiating effect of rapamycin on all-trans-retinoic acid (ATRA)-mediated differentiation of acute myelogenous leukemia (AML) cells, prompting us to investigate the effects of longitudinal inhibition of PI3K/Akt/mTOR signaling pathway on both proliferation and differentiative capacity of AML. In NB4, HL-60, U937 and K562 cell lines, rapamycin exerted minimal antiproliferative effects, and combining PI3K inhibitor LY 294002 and rapamycin inhibited proliferation more than LY 294002 alone. Rapamycin potentiated differentiation of ATRA-treated NB4 cells, but the combination of rapamycin and LY 294002 inhibited the expression of CD11b in both ATRA- and phorbol myristate acetate (PMA)-stimulated cells more than PI3K inhibitor alone. These results demonstrate that, although the combination of PI3K inhibitor and rapamycin is more effective in inhibiting proliferation of AML, the concomitant inhibition of PI3K and mTOR by LY 294002 and rapamycin has more inhibitory effects on ATRA-mediated differentiation than the presence of PI3K-inhibitor alone, and diminishes positive effects of rapamycin on leukemia cell differentiation.

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Abbreviations

PI3K:

Phosphatydilinositol 3-kinase

mTOR:

Mammalian target of rapamycin

AML:

Acute myelogenous leukemia

MAPK/ERK:

Mitogen-activated protein kinase/extracellular signal-regulated kinase

APL:

Acute promyelocytic leukemia

ATRA:

All-trans-retinoic acid

PMA:

Phorbol myristate acetate

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Acknowledgements

We thank Ms Dunja Tankovic for valuable technical help and assistance. 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.).

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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, 10 000, Zagreb, Croatia

    Josko Mise, Vilma Dembitz, Hrvoje Banfic & Dora Visnjic

  2. Zavod za fiziologiju, Medicinski fakultet, Sveuciliste u Zagrebu, Salata 3, POB 978, 10 001, Zagreb, Croatia

    Dora Visnjic

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  1. Josko Mise
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Correspondence to Dora Visnjic.

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Mise, J., Dembitz, V., Banfic, H. et al. Combined Inhibition of PI3K and mTOR Exerts Synergistic Antiproliferative Effect, but Diminishes Differentiative Properties of Rapamycin in Acute Myeloid Leukemia Cells. Pathol. Oncol. Res. 17, 645–656 (2011). https://doi.org/10.1007/s12253-011-9365-z

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  • DOI: https://doi.org/10.1007/s12253-011-9365-z

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