Document Detail


Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells.
MedLine Citation:
PMID:  19359162     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Tina X Lee; Mark D Packer; Jie Huang; Elena M Akhmametyeva; Samuel K Kulp; Ching-Shih Chen; Marco Giovannini; Abraham Jacob; D Bradley Welling; Long-Sheng Chang
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2009-04-07
Journal Detail:
Title:  European journal of cancer (Oxford, England : 1990)     Volume:  45     ISSN:  1879-0852     ISO Abbreviation:  Eur. J. Cancer     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-06-01     Completed Date:  2009-07-07     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  9005373     Medline TA:  Eur J Cancer     Country:  England    
Other Details:
Languages:  eng     Pagination:  1709-20     Citation Subset:  IM    
Affiliation:
Department of Otolaryngology, The Ohio State University College of Medicine, Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
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MeSH Terms
Descriptor/Qualifier:
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,  pathology*
Neuroma, Acoustic / metabolism,  pathology
Phosphorylation / drug effects
Protein Kinase Inhibitors / pharmacology*
Protein-Serine-Threonine Kinases / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism
Pyrazoles / pharmacology*
Schwann Cells / cytology,  drug effects
Signal Transduction / drug effects
Sulfonamides / pharmacology*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
R01 DC005985-04/DC/NIDCD NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/OSU 03012; 0/Protein Kinase Inhibitors; 0/Pyrazoles; 0/Sulfonamides; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.2/pyruvate dehydrogenase (acetyl-transferring) kinase
Comments/Corrections

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