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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.

SUBMITTER: Burns SS

PROVIDER: S-EPMC3549000 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Histone deacetylase inhibitor AR-42 differentially affects cell-cycle transit in meningeal and meningioma cells, potently inhibiting NF2-deficient meningioma growth.

Burns Sarah S SS Akhmametyeva Elena M EM Oblinger Janet L JL Bush Matthew L ML Huang Jie J Senner Volker V Chen Ching-Shih CS Jacob Abraham A Welling D Bradley DB Chang Long-Sheng LS

Cancer research 20121114 2

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 ...[more]

PMID: 23151902

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Project description:ObjectivePancreatic cancer is one of the most lethal types of cancer with a 5-year survival rate of ~5%. Histone deacetylases (HDACs) participate in many cellular processes, including carcinogenesis, and pharmacological inhibition of HDACs has emerged as a potential therapeutic strategy. In this study, we explored antitumor activity of the novel HDAC inhibitor AR-42 in pancreatic cancer.MethodsHuman pancreatic cancer cell lines BxPC-3 and PANC-1 were used in this study. Real-time PCR, RT-PCR, and western blotting were employed to investigate expression of specific genes and proteins, respectively. Translocation of apoptosis-inducing factor was investigated by immunofluorescence and subcellular fractionation. The number of apoptotic cells, cell cycle stages, and reactive oxygen species (ROS) generation levels were determined by flow cytometry. Cell invasiveness was examined by the Matrigel invasion assay. Efficacy of AR-42 in vivo was evaluated by utilizing BxPC-3 xenograft mouse model.ResultsAR-42 inhibited pancreatic cancer cell proliferation by causing G2/M cell cycle arrest via regulating expression levels of genes and proteins involved in cell cycle. AR-42 also induced ROS generation and DNA damage, triggering apoptosis of pancreatic cancer cells via both caspase-3-dependent and caspase-3-independent pathways. In addition, AR-42 increased expression levels of negative regulators of p53 (miR-125b, miR-30d, and miR33), which could contribute to lower expression level of mutant p53 in pancreatic cancer cells. Cell invasion assay showed that AR-42 reduced cancer cell aggressiveness and significantly diminished BxPC-3 xenograft tumor growth in vivo.ConclusionAR-42, a novel HDAC inhibitor, inhibited pancreatic cancer cells by regulating p53 expression, inducing cell cycle arrest, particularly at the G2/M stage, and activating multiple apoptosis pathways. Additionally, AR-42 inhibited cell invasiveness and potently suppressed pancreatic cancer tumors in vivo. We conclude that by virtue of its multiple mechanisms of action, AR-42 possesses a considerable potential as an antitumor agent in pancreatic cancer.

Dataset Information

Histone deacetylase inhibitor AR-42 differentially affects cell-cycle transit in meningeal and meningioma cells, potently inhibiting NF2-deficient meningioma growth.

Publications

Histone deacetylase inhibitor AR-42 differentially affects cell-cycle transit in meningeal and meningioma cells, potently inhibiting NF2-deficient meningioma growth.

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