title: Histone deacetylase inhibitor AR-42 differentially affects cell-cycle transit in meningeal and meningioma cells, potently inhibiting NF2-deficient meningioma growth.
abstract: Meningiomas constitute about 34% of primary intracranial tumors and are associated with increased mortality in patients with neurofibromatosis type 2 (NF2). To evaluate potential medical therapies for these tumors, we have established a quantifiable orthotopic model for NF2-deficient meningiomas. We showed that telomerase-immortalized Ben-Men-1 benign meningioma cells harbored a single nucleotide deletion in NF2 exon 7 and did not express the NF2 protein, merlin. We also showed that AR-42, a pan-histone deacetylase inhibitor, inhibited proliferation of both Ben-Men-1 and normal meningeal cells by increasing expression of p16(INK4A), p21(CIP1/WAF1), and p27(KIP1). In addition, AR-42 increased proapoptotic Bim expression and decreased anti-apoptotic Bcl(XL) levels. However, AR-42 predominantly arrested Ben-Men-1 cells at G(2)-M whereas it induced cell-cycle arrest at G(1) in meningeal cells. Consistently, AR-42 substantially decreased the levels of cyclin D1, E, and A, and proliferating cell nuclear antigen in meningeal cells while significantly reducing the expression of cyclin B, important for progression through G(2), in Ben-Men-1 cells. In addition, AR-42 decreased Aurora A and B expression. To compare the in vivo efficacies of AR-42 and AR-12, a PDK1 inhibitor, we generated and used luciferase-expressing Ben-Men-1-LucB cells to establish intracranial xenografts that grew over time. While AR-12 treatment moderately slowed tumor growth, AR-42 caused regression of Ben-Men-1-LucB tumors. Importantly, AR-42-treated tumors showed minimal regrowth when xenograft-bearing mice were switched to normal diet. Together, these results suggest that AR-42 is a potential therapy for meningiomas. The differential effect of AR-42 on cell-cycle progression of normal meningeal and meningioma cells may have implications for why AR-42 is well-tolerated while it potently inhibits tumor growth.
authors.affiliation: Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital; Department of Otolaryngology, The Ohio State University College of Medicine, Columbus, Ohio, USA 43205.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Burns
authors.forename: Elena M
authors.initials: EM
authors.lastname: Akhmametyeva
authors.forename: Janet L
authors.initials: JL
authors.lastname: Oblinger
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Bush
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Volker
authors.initials: V
authors.lastname: Senner
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Abraham
authors.initials: A
authors.lastname: Jacob
authors.forename: D Bradley
authors.initials: DB
authors.lastname: Welling
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Chang
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016515:Genes, Neurofibromatosis 2; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000473:pathology; D008578:Meninges / Q000187:drug effects*; D008579:Meningioma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010654:Phenylbutyrates / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates