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

Matthew L. Bush, Janet Oblinger, Victoria Brendel, Griffin Santarelli, Jie Huang, Elena M. Akhmametyeva, Sarah S. Burns, Justin Wheeler, Jeremy Davis, Charles Yates, Abhik R. Chaudhury, Samuel Kulp, Ching Shih Chen, Long Sheng Chang, D. Bradley Welling, Abraham Jacob

Research output: Contribution to journalArticle

35 Citations (Scopus)

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 (IC50) of 500 nM and 250-350 nM, respectively. AR42 also inhibited primary meningioma cells and the benign meningioma cell line, Ben-Men-1, with IC50 values of 1.5 mM and 1.0 mM, respectively. AR42 treatment induced cell-cycle arrest at G2 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.

Original languageEnglish (US)
Pages (from-to)983-999
Number of pages17
JournalNeuro-Oncology
Volume13
Issue number9
DOIs
StatePublished - Sep 2011
Externally publishedYes

Fingerprint

Histone Deacetylase Inhibitors
Acoustic Neuroma
Meningioma
Neurilemmoma
Neurofibromatosis 2
Therapeutics
Growth
Heterografts
Inhibitory Concentration 50
G2 Phase Cell Cycle Checkpoints
Apoptosis
Tumor Burden
Pharmaceutical Preparations
Neoplasms
Cell Cycle
Flow Cytometry
Phosphotransferases
Western Blotting
Immunohistochemistry
Cell Line

Keywords

  • Akt
  • AR42
  • Cell-cycle arrest
  • HDAC inhibitors (HDACis)
  • Meningiomas
  • Merlin
  • Neurofibromatosis type 2 (NF2)
  • NF2 gene
  • Vestibular schwannomas (VS)

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Bush, M. L., Oblinger, J., Brendel, V., Santarelli, G., Huang, J., Akhmametyeva, E. M., ... Jacob, A. (2011). AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas. Neuro-Oncology, 13(9), 983-999. https://doi.org/10.1093/neuonc/nor072

AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas. / Bush, Matthew L.; Oblinger, Janet; Brendel, Victoria; Santarelli, Griffin; Huang, Jie; Akhmametyeva, Elena M.; Burns, Sarah S.; Wheeler, Justin; Davis, Jeremy; Yates, Charles; Chaudhury, Abhik R.; Kulp, Samuel; Chen, Ching Shih; Chang, Long Sheng; Welling, D. Bradley; Jacob, Abraham.

In: Neuro-Oncology, Vol. 13, No. 9, 09.2011, p. 983-999.

Research output: Contribution to journalArticle

Bush, ML, Oblinger, J, Brendel, V, Santarelli, G, Huang, J, Akhmametyeva, EM, Burns, SS, Wheeler, J, Davis, J, Yates, C, Chaudhury, AR, Kulp, S, Chen, CS, Chang, LS, Welling, DB & Jacob, A 2011, 'AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas', Neuro-Oncology, vol. 13, no. 9, pp. 983-999. https://doi.org/10.1093/neuonc/nor072
Bush, Matthew L. ; Oblinger, Janet ; Brendel, Victoria ; Santarelli, Griffin ; Huang, Jie ; Akhmametyeva, Elena M. ; Burns, Sarah S. ; Wheeler, Justin ; Davis, Jeremy ; Yates, Charles ; Chaudhury, Abhik R. ; Kulp, Samuel ; Chen, Ching Shih ; Chang, Long Sheng ; Welling, D. Bradley ; Jacob, Abraham. / AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas. In: Neuro-Oncology. 2011 ; Vol. 13, No. 9. pp. 983-999.
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