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.