Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells

Eur J Cancer. 2009 Jun;45(9):1709-20. doi: 10.1016/j.ejca.2009.03.013. Epub 2009 Apr 7.

Abstract

Background: Vestibular schwannomas (VS) frequently express high levels of activated AKT. Small-molecule inhibitors of AKT signalling may have therapeutic potential in suppressing the growth of benign VS and malignant schwannomas.

Method: Primary VS and Schwann cells, human malignant schwannoma HMS-97 cells and mouse Nf2(-/-) Schwann cells and schwannoma cells were prepared to investigate the growth inhibitory and anti-tumour activities of OSU-03012, a celecoxib-derived small-molecule inhibitor of phosphoinositide-dependent kinase-1. Cell proliferation assays, apoptosis, Western blot, in vivo xenograft analysis using SCID mice and immunohistochemistry were performed.

Results: OSU-03012 inhibited cell proliferation more effectively in both VS and HMS-97 cells than in normal human Schwann cells. The IC5) of OSU-03012 at 48h was approximately 3.1 microM for VS cells and 2.6 microM for HMS-97 cells, compared with the IC(50) of greater than 12 microM for human Schwann cells. Similarly, mouse Nf2(-/-) schwannoma and Nf2(-/-) Schwann cells were more sensitive to growth inhibition by OSU-03012 than wild-type mouse Schwann cells and mouse schwannoma cells established from transgenic mice carrying the NF2 promoter-driven SV40 T-antigen gene. Like VS cells, malignant schwannoma HMS-97 cells expressed high levels of activated AKT. OSU-03012 induced apoptosis in both VS and HMS-97 cells and caused a marked reduction of AKT phosphorylation at both the Ser-308 and Thr-473 sites in a dose-dependent manner. In vivo xenograft analysis showed that OSU-03012 was well tolerated and inhibited the growth of HMS-97 schwannoma xenografts by 55% after 9 weeks of oral treatment. The anti-tumour activity correlated with reduced AKT phosphorylation.

Conclusion: OSU-03012 is a potential chemotherapeutic agent for VS and malignant schwannomas.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Mice
  • Mice, SCID
  • Mice, Transgenic
  • Neurilemmoma / metabolism
  • Neurilemmoma / pathology*
  • Neuroma, Acoustic / metabolism
  • Neuroma, Acoustic / pathology
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazoles / pharmacology*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Schwann Cells / cytology
  • Schwann Cells / drug effects
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • OSU 03012
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Sulfonamides
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt