Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Int J Cancer. 2011 Dec 15;129(12):2958-65. doi: 10.1002/ijc.26268. Epub 2011 Aug 29.

Abstract

Activation of the PI3K/Akt signaling pathway is correlated with poor prognosis in neuroblastoma, the most common and deadly extracranial tumor of childhood. In this study, we show that the small-molecule inhibitors of phosphoinositide-dependent protein kinase-1 (PDK1) OSU03012 and the dual class I PI3K/mTOR inhibitor PI103 have profound effects on neuroblastoma survival in vitro and in vivo. Both OSU03012 and PI103 inhibited neuroblastoma growth in vitro. In treated cells, OSU03012 induced apoptosis and an S phase cell cycle arrest, whereas only minor apoptosis was detected in PI103 treated cells together with a G1 arrest. Both OSU03012 and PI103 downregulated phosphorylation of Akt and inhibited the downstream targets glycogen synthase kinase-3β (GSK3β) and p70 S6 kinase-1 (S6K1), as well as downregulated the expression of cyclin D1 and Mycn protein. Neuroblastoma cells expressing high levels of Mycn were more sensitive to OSU03012 or PI103 compared with cells expressing low Mycn levels. Both compounds significantly inhibited the growth of established, subcutaneous MYCN-amplified neuroblastoma xenografts in nude NMRI nu/nu mice. These results suggest that inhibition of the PI3K/Akt signaling pathway represent a clinical relevant target for the treatment of patients with high-risk MYCN-amplified neuroblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cyclin D1 / metabolism
  • Furans / pharmacology*
  • Humans
  • Mice
  • Mice, Nude
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma / metabolism*
  • Nuclear Proteins / metabolism
  • Oncogene Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazoles / pharmacology*
  • Pyridines / pharmacology*
  • Pyrimidines / pharmacology*
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Signal Transduction / drug effects*
  • Sulfonamides / pharmacology*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • CCND1 protein, human
  • Furans
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • OSU03013
  • Oncogene Proteins
  • PDK1 protein, human
  • PI103
  • Pdk1 protein, mouse
  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Sulfonamides
  • Cyclin D1
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt