Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells.
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-9...
| Publicado en: | European Journal of Cancer Vol. 45; no. 9; pp. 1709 - 1721 |
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| Autores principales: | , , , , , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
Pergamon Press - An Imprint of Elsevier Science
Jun2009
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=105367209&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 105367209 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 09598049 1VW jtl: European Journal of Cancer issn: 09598049 maglogo: N pubinfo: dt: Jun2009 vid: 45 iid: 9 pid: 2410 pub: Pergamon Press - An Imprint of Elsevier Science artinfo: ui: 105367209 2010325650 10.1016/j.ejca.2009.03.013 NLM19359162 105367209 ppf: 1709 ppct: 12 formats: tig: atl: Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells. aug: au: Lee TX Packer MD Huang J Akhmametyeva EM Kulp SK Chen C Giovannini M Jacob A Welling DB Chang L affil: 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. sug: subj: Cells Growth Substances Physiology Neuroma, Acoustic Diagnosis Apoptosis Biological Assay Blotting, Western Europe Funding Source Grafts Immunohistochemistry Magnetic Resonance Imaging Methods Human ab: 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. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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