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. 2008 Sep;22(9):1728-36. doi: 10.1038/leu.2008.158. Epub 2008 Jun 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Drug Synergism
  • Furans / pharmacology
  • Gene Expression Regulation / drug effects
  • Humans
  • Imidazoles / pharmacology
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Mitochondrial Proteins / drug effects
  • Phosphoinositide-3 Kinase Inhibitors*
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / drug effects*
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • TOR Serine-Threonine Kinases
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / drug effects*
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Furans
  • Imidazoles
  • Mitochondrial Proteins
  • PI103
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Tumor Suppressor Protein p53
  • nutlin 3
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases