Treatment options for patients with vestibular schwannomas (VS) and meningiomas include surgical excision and radiation; however, no medical therapies exist. The purposes of this research are 1) to identify novel therapeutics that inhibit VS and meningioma growth, and 2) to inhibit upregulated pathways involved in tumorigenesis.
Methods
Human VS cells were cultured and treated with a novel histone deacetylase (HDAC) inhibitor, HDAC-42, a commercially available HDAC inhibitor, SAHA, and an epidermal growth factor receptor (EGFR) inhibitor, erlotinib. MTS proliferation assays were utilized to assess cell proliferation and 50-percent inhibitory concentration (IC50) of each drug. Primary human meningioma cells and benign and malignant human meningioma cell lines were also drug-treated and response was evaluated. Receptor tyrosine kinase arrays were performed to indentify tumor pathways. The effects on molecular signaling pathways were analyzed by Western Blot.
Results
VS and meningiomas expressed high-levels of activated AKT. HDAC-42 potently inhibited the proliferation of VS cells by inhibiting phosphorylation of AKT and inducing apoptosis. Meningioma cells treated with HDAC-42 were also found to have an IC50 in the low micromolar range, and the treatment led to an inhibition of phosphorylated AKT. Both VS and meningioma cells expressed EGFR; however, higher micromolar doses of erlotinib were required for growth inhibition.
Conclusions
Human VS and meningioma cells are sensitive to in vitro treatment with HDAC-42, which appears to downregulate the AKT pathway. Further investigation on the molecular targets of these chemotherapeutic agents will be pursued.
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