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.
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.
Tina X
TX
Lee
Mark D
MD
Packer
Jie
J
Huang
Elena M
EM
Akhmametyeva
Samuel K
SK
Kulp
Ching-Shih
CS
Chen
Marco
M
Giovannini
Abraham
A
Jacob
D Bradley
DB
Welling
Long-Sheng
LS
Chang
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