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Apoptosis

The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML

Leukemia volume 22, pages 1728–1736 (2008)Cite this article

Abstract

Activation of the phosphatidylinositol-3 kinase/Akt/mammalian target of the rapamycin (PI3K/Akt/mTOR) pathway and inactivation of wild-type p53 by murine double minute 2 homologue (Mdm2) overexpression are frequent molecular events in acute myeloid leukemia (AML). We investigated the interaction of PI3K/Akt/mTOR and p53 pathways after their simultaneous blockade using the dual PI3K/mTOR inhibitor PI-103 and the Mdm2 inhibitor Nutlin-3. We found that PI-103, which itself has modest apoptogenic activity, acts synergistically with Nutlin-3 to induce apoptosis in a wild-type p53-dependent fashion. PI-103 synergized with Nutlin-3 to induce Bax conformational change and caspase-3 activation, despite its inhibitory effect on p53 induction. The PI-103/Nutlin-3 combination caused profound dephosphorylation of 4E-BP1 and decreased expression of many proteins including Mdm2, p21, Noxa, Bcl-2 and survivin, which can affect mitochondrial stability. We suggest that PI-103 actively enhances downstream p53 signaling and that a combination strategy aimed at inhibiting PI3K/Akt/mTOR signaling and activating p53 signaling is potentially effective in AML, where TP53 mutations are rare and downstream p53 signaling is intact.

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Acknowledgements

We acknowledge Dr Maria Soengas of Department of Dermatology, University of Michigan, Ann Arbor, MI, USA for kindly providing retrovirus encoding p53-specific shRNA. KK was supported in part by grants from the Kanae Foundation For Life and Socio-Medical Science and Novartis Foundation (Japan) for the Promotion of Science, MA by the Paul and Mary Haas Chair in Genetics and a grant from NIH, CA55164 and CA100632.

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Authors and Affiliations

  1. Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

    K Kojima, M Shimanuki, N Hanaoka & H Nakakuma

  2. Department of Hematology, Aichi Medical University School of Medicine, Aichi, Japan

    M Shikami

  3. Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA

    I J Samudio, V Ruvolo, M Konopleva & M Andreeff

  4. Genitourinary Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA

    P Corn

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Kojima, K., Shimanuki, M., Shikami, M. et al. The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia 22, 1728–1736 (2008). https://doi.org/10.1038/leu.2008.158

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