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.


METHODS
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.


CONCLUSIONS
OSU-03012 is a potential chemotherapeutic agent for VS and malignant schwannomas.
Lee
Tina X
TX
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.
Packer
Mark D
MD
Huang
Jie
J
Akhmametyeva
Elena M
EM
Kulp
Samuel K
SK
Chen
Ching-Shih
CS
Giovannini
Marco
M
Jacob
Abraham
A
Welling
D Bradley
DB
Chang
Long-Sheng
LS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009442:Neurilemmoma / Q000378:metabolism / Q000473:pathology*; D009464:Neuroma, Acoustic / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012583:Schwann Cells / Q000166:cytology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C500894:OSU 03012; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013449:Sulfonamides; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt