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Acute Leukemias

Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia

Leukemia volume 26, pages 910–917 (2012)Cite this article

Abstract

Although TP53 mutations are rare in acute myeloid leukemia (AML), wild type p53 function is habitually annulled through overexpression of MDM2 or through various mechanisms including epigenetic silencing by histone deacetylases (HDACs). We hypothesized that co-inhibition of MDM2 and HDACs, with nutlin-3 and valproic acid (VPA) would additively inhibit growth in leukemic cells expressing wild type TP53 and induce p53-mediated apoptosis. In vitro studies with the combination demonstrated synergistic induction of apoptosis in AML cell lines and patient cells. Nutlin-3 and VPA co-treatment resulted in massive induction of p53, acetylated p53 and p53 target genes in comparison with either agent alone, followed by p53 dependent cell death with autophagic features. In primary AML cells, inhibition of proliferation by the combination therapy correlated with the CD34 expression level of AML blasts. To evaluate the combination in vivo, we developed an orthotopic, NOD/SCID IL2rγnull xenograft model of MOLM-13 (AML FAB M5a; wild type TP53) expressing firefly luciferase. Survival analysis and bioluminescent imaging demonstrated the superior in vivo efficacy of the dual inhibition of MDM2 and HDAC in comparison with controls. Our results suggest the concomitant targeting of MDM2-p53 and HDAC inhibition, may be an effective therapeutic strategy for the treatment of AML.

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Acknowledgements

This study was supported by The Norwegian Cancer Society (Kreftforeningen), The Western Norway Regional Health Authority (E.Mc.C. and B.T.G.) and Bergen Research Foundation. We thank Lena F Hansen, Lene M Vikebø, Michaela Popa, Maren Boge, Kjetil Jacobsen, Jørn Skavland, Bjarte S Erikstein, Andre Sulen, Paulina Ruurs, Lasse Evensen, Marianne Enger, Randi Hovland, Harald Valen, Lars Helgeland, Edith Fick, Line Bjørge, Liv Cecilie Vestrheim and Reidar Myklebust for discussion, expert advice and technical assistance. The optical imaging and transmission electron microscopy was performed at the Molecular Imaging Center (FUGE, Norwegian Research Council), University of Bergen.

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Authors and Affiliations

  1. Department of Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway

    E McCormack, Ø Bruserud & B T Gjertsen

  2. Institute of Medicine, Hematology Section, University of Bergen, Bergen, Norway

    E McCormack, I Haaland, G Venås, R B Forthun, Ø Bruserud & B T Gjertsen

  3. Department of Biomedicine, University of Bergen, Bergen, Norway

    S Huseby, G Gausdal, D R Micklem & J B Lorens

  4. Institute of Medicine, Section of Oncology, University of Bergen, Bergen, Norway

    S Knappskog

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  1. E McCormack
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Correspondence to B T Gjertsen.

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McCormack, E., Haaland, I., Venås, G. et al. Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia. Leukemia 26, 910–917 (2012). https://doi.org/10.1038/leu.2011.315

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