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

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

Research output: Contribution to journalArticle

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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 IC50 of OSU-03012 at 48 h was approximately 3.1 μM for VS cells and 2.6 μM for HMS-97 cells, compared with the IC50 of greater than 12 μM 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.

Original languageEnglish (US)
Pages (from-to)1709-1720
Number of pages12
JournalEuropean Journal of Cancer
Volume45
Issue number9
DOIs
StatePublished - Jun 2009
Externally publishedYes

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Acoustic Neuroma
Neurilemmoma
Schwann Cells
Growth
Neoplasms
Heterografts
Celecoxib
Inhibitory Concentration 50
Phosphorylation
Cell Proliferation
Apoptosis
Polyomavirus Transforming Antigens
OSU 03012
1-Phosphatidylinositol 4-Kinase
SCID Mice
Transgenic Mice
Western Blotting
Immunohistochemistry

Keywords

  • Cyclooxygenase-2 inhibitor
  • Malignant schwannoma HMS-97
  • Merlin
  • Neurofibromatosis type 2
  • OSU-03012
  • Phosphoinositide-dependent kinase-1
  • PI3K/AKT pathway
  • The Neurofibromatosis 2 (NF2) gene
  • Vestibular schwannoma
  • Xenograft

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells. / Lee, Tina X.; Packer, Mark D.; Huang, Jie; Akhmametyeva, Elena M.; Kulp, Samuel K.; Chen, Ching Shih; Giovannini, Marco; Jacob, Abraham; Welling, D. Bradley; Chang, Long Sheng.

In: European Journal of Cancer, Vol. 45, No. 9, 06.2009, p. 1709-1720.

Research output: Contribution to journalArticle

Lee, TX, Packer, MD, Huang, J, Akhmametyeva, EM, Kulp, SK, Chen, CS, Giovannini, M, Jacob, A, Welling, DB & Chang, LS 2009, 'Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells', European Journal of Cancer, vol. 45, no. 9, pp. 1709-1720. https://doi.org/10.1016/j.ejca.2009.03.013
Lee, Tina X. ; Packer, Mark D. ; Huang, Jie ; Akhmametyeva, Elena M. ; Kulp, Samuel K. ; Chen, Ching Shih ; Giovannini, Marco ; Jacob, Abraham ; Welling, D. Bradley ; Chang, Long Sheng. / Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells. In: European Journal of Cancer. 2009 ; Vol. 45, No. 9. pp. 1709-1720.
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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 IC50 of OSU-03012 at 48 h was approximately 3.1 μM for VS cells and 2.6 μM for HMS-97 cells, compared with the IC50 of greater than 12 μM 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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AU - Huang, Jie

AU - Akhmametyeva, Elena M.

AU - Kulp, Samuel K.

AU - Chen, Ching Shih

AU - Giovannini, Marco

AU - Jacob, Abraham

AU - Welling, D. Bradley

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N2 - 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 IC50 of OSU-03012 at 48 h was approximately 3.1 μM for VS cells and 2.6 μM for HMS-97 cells, compared with the IC50 of greater than 12 μM 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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KW - Phosphoinositide-dependent kinase-1

KW - PI3K/AKT pathway

KW - The Neurofibromatosis 2 (NF2) gene

KW - Vestibular schwannoma

KW - Xenograft

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