9
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas.

      Neuro-Oncology

      Animals, Apoptosis, drug effects, Blotting, Western, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, Fluorescent Antibody Technique, Histone Deacetylase Inhibitors, therapeutic use, Humans, Immunoenzyme Techniques, Magnetic Resonance Imaging, Meningeal Neoplasms, drug therapy, metabolism, pathology, Meningioma, Mice, Mice, Knockout, Mice, SCID, Neurofibromatosis 2, Neurofibromin 2, physiology, Neuroma, Acoustic, Phenylbutyrates, Phosphorylation, Protein Array Analysis, Proto-Oncogene Proteins c-akt, Signal Transduction, Survival Rate

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Neurofibromatosis type 2 (NF2) is an autosomal-dominant disease that results in the formation of bilateral vestibular schwannomas (VSs) and multiple meningiomas. Treatment options for NF2-associated tumors are limited, and to date, no medical therapies are FDA approved. The ideal chemotherapeutic agent would inhibit both VS and meningiomas simultaneously. The objectives of this study are (1) to test the efficacy of AR42, a novel histone deacetylase inhibitor, to inhibit VS and meningioma growth and (2) to investigate this drug's mechanisms of action. Primary cultures of human VS and meningioma cells were established. Nf2-deficient mouse schwannoma and benign human meningioma Ben-Men-1 cells were also cultured. Cells were treated with AR42, and the drug's effects on proliferation and the cell cycle were analyzed using a methanethiosulfonate assay and flow cytometry, respectively. Human phospho-kinase arrays and Western blots were used to evaluate the effects of AR42 on intracellular signaling. The in vivo efficacy of AR42 was investigated using schwannoma xenografts. Tumor volumes were quantified using high-field, volumetric MRI, and molecular target analysis was performed using immunohistochemistry. AR42 inhibited the growth of primary human VS and Nf2-deficient mouse schwannoma cells with a half maximal inhibitory concentration (IC(50)) of 500 nM and 250-350 nM, respectively. AR42 also inhibited primary meningioma cells and the benign meningioma cell line, Ben-Men-1, with IC(50) values of 1.5 µM and 1.0 µM, respectively. AR42 treatment induced cell-cycle arrest at G(2) and apoptosis in both VS and meningioma cells. Also, AR42 exposure decreased phosphorylated Akt in schwannoma and meningioma cells. In vivo treatment with AR42 inhibited the growth of schwannoma xenografts, induced apoptosis, and decreased Akt activation. The potent growth inhibitory activity of AR42 in schwannoma and meningioma cells suggests that AR42 should be further evaluated as a potential treatment for NF2-associated tumors.

          Related collections

          Author and article information

          Journal
          21778190
          3158011
          10.1093/neuonc/nor072

          Comments

          Comment on this article