title: AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas.
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.
authors.affiliation: Department of Otolaryngology–Head and Neck Surgery, The Ohio State University, Columbus, OH 43212, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Bush
authors.forename: Janet
authors.initials: J
authors.lastname: Oblinger
authors.forename: Victoria
authors.initials: V
authors.lastname: Brendel
authors.forename: Griffin
authors.initials: G
authors.lastname: Santarelli
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Elena M
authors.initials: EM
authors.lastname: Akhmametyeva
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Burns
authors.forename: Justin
authors.initials: J
authors.lastname: Wheeler
authors.forename: Jeremy
authors.initials: J
authors.lastname: Davis
authors.forename: Charles W
authors.initials: CW
authors.lastname: Yates
authors.forename: Abhik R
authors.initials: AR
authors.lastname: Chaudhury
authors.forename: Samuel
authors.initials: S
authors.lastname: Kulp
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Chang
authors.forename: D Bradley
authors.initials: DB
authors.lastname: Welling
authors.forename: Abraham
authors.initials: A
authors.lastname: Jacob
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008579:Meningioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D016518:Neurofibromatosis 2 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D025581:Neurofibromin 2 / Q000502:physiology; D009464:Neuroma, Acoustic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010654:Phenylbutyrates / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D040081:Protein Array Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D056572:Histone Deacetylase Inhibitors; D025581:Neurofibromin 2; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; D051057:Proto-Oncogene Proteins c-akt