osu-03012 and Neurilemmoma

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.. 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.. 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.. OSU-03012 is a potential chemotherapeutic agent for VS and malignant schwannomas.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Mice; Mice, SCID; Mice, Transgenic; Neurilemmoma; Neuroma, Acoustic; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Schwann Cells; Signal Transduction; Sulfonamides; Tumor Cells, Cultured; Xenograft Model Antitumor Assays