| Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells. | |
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MedLine Citation:
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PMID: 19359162 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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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:
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Title: European journal of cancer (Oxford, England : 1990) Volume: 45 ISSN: 1879-0852 ISO Abbreviation: Eur. J. Cancer Publication Date: 2009 Jun |
Date Detail:
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Created Date: 2009-06-01 Completed Date: 2009-07-07 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 9005373 Medline TA: Eur J Cancer Country: England |
Other Details:
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Languages: eng Pagination: 1709-20 Citation Subset: IM |
Affiliation:
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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. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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R01 DC005985-04/DC/NIDCD NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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