Inhibitors of histone deacetylases as potential therapeutic tools for high‐risk embryonal tumors of the nervous system of childhood

Abstract

The origin of malignant embryonal tumors is incompletely understood and certain risk groups remain difficult to treat. The epigenetic structure of DNA and its lesions play a role in the origin of these neoplasms. Manipulation of the epigenome may offer novel treatment options. The authors evaluated the cytotoxicity of histone deacetylase inhibitors (HDI) [MS-275, SAHA, TSA, M344, M360, D85, SW55, SW187 and valproic acid (VPA)] on 13 embryonal tumor cell lines [4 medulloblastomas, 5 neuroblastomas, 2 atypical teratoid/rhabdoid tumors (AT/RT), and 2 malignant rhabdoid tumors of the kidney (RTK)] in MTT assay. In addition, HDI effects on hyperacetylation, reexpression of growth regulatory genes and apoptosis were characterized by Western analysis, RT-PCR and annexin-V staining. All HDI inhibited cell proliferation in a time-and dose-dependent manner. VPA was least cytotoxic with GI 50 values after 72 hr ranging from 53.6 to 332.9 lM, while TSA was most efficient with GI 50 values after 72 hr ranging from 0.01 to 8.8 lM. M344 and M360 were also highly effective. Western blot revealed hyperacetylation of histone H4 after HDI treatment. Reactivation of several genes including the proapoptotic CASP8 was identified by RT-PCR. Annexin-V staining demonstrated a dose and time dependent induction of apoptosis. HDI inhibited the growth of medulloblastoma, neuroblastoma and rhabdoid tumors in vitro. Treatment with HDI induced the reactivation of growth regulatory genes and consequently apoptosis. Our results warrant further studies and may help in the design of new protocols geared at the treatment of high risk embryonal tumors. ' 2007 Wiley-Liss, Inc.

Low-Dose Histone Deacetylase Inhibitor Treatment Leads to Tumor Growth Arrest and Multi-Lineage Differentiation of Malignant Rhabdoid Tumors

“…A reference wavelength of 620 nm was used for subtraction of background absorbance. Drug concentrations that achieved 50% growth inhibition (GI 50 ) were calculated as described previously (21).…”

“…Several studies now suggest that histone acetylation events are a key element of SMARCB1 function and MRT pathogenesis, leading to the study of histone de-acetylase inhibitors as potential therapy for MRT (8,(20)(21)(22)(23)(24). However, these studies have focused on HDACi as "cytotoxics" rather than differentiating agents.…”

Epigenetic mechanisms regulating neural development and pediatric brain tumor formation

“…The same group evaluated the effects of HDAC inhibitors in embryonal tumor cell lines demonstrating a dose-and time-dependent apoptosis. 45 Recently, Sredni and coworkers 131 described the upregulation of miRNA-221 and miRNA-222 in AT/RT. These two miRNAs were previously identified as negative regulators of p27 Kip1 , a member of the CDK family that inhibits cell cycle progression.…”

HDAC5 and HDAC9 in Medulloblastoma: Novel Markers for Risk Stratification and Role in Tumor Cell Growth

“…A wide body of literature provides evidence for effective treatment of different tumor cells using HDAC inhibitors (HDACi) in vitro and in vivo, such as leukemia (8), lymphoma (9), lung cancer (10,11), retinoblastoma (12), and neuroblastoma (13,14). Brain tumor cells seem to be susceptible to treatment with HDACi as has been shown for glioblastoma (15,16), atypical teratoid/rhabdoid tumor (17), and medulloblastoma (17)(18)(19). HDACis have only recently been introduced in the clinical setting of cancer treatment, with Vorinostat being the first HDACi approved for the treatment of cutaneous T-cell lymphoma by the Food and Drug Administration (20).…”