Malignant gliomas are associated with a high morbidity and mortality. Among several therapeutic strategies being explored to improve the outcome of this disease, chromatin modulation by inhibiting histone deacetylase (HDAC) activity is novel approach that has shown efficacy in preclinical studies and is currently being tested in clinical trials. SAHA is a potent HDAC inhibitor that has shown activity against several malignancies in preclinical studies; preliminary data from clinical trials have suggested promising activity and tolerability in humans. We examined the effects of SAHA on glioma cells (Hs683, D54MG, U373MG and U87MG) and normal human astrocytes (NHA) to determine the mechanism of action and impact on tumor biology in vitro. Treatment with SAHA resulted in decreased proliferation and induction of apoptosis induction in a dose- and time-dependent manner. SAHA-treated glioma cells showed decreased anchorage-independent growth compared with untreated controls. SAHA also caused hyperacetylation of histone H3 and H4. Exposure to SAHA was not associated with significant changes in p53 levels or in components of the DNA damage signaling pathway suggesting that the effects of SAHA were not primarily a result of DNA damage. However, SAHA induced an increase in levels of expression of p21/Cip1, and a disruption of the cyclin B1/cdc2 activity resulting in accumulation of cells in the G2 phase of the cell cycle and subsequent induction of apoptosis.These results indicate that SAHA acts primarily by altering levels of proteins in the G2 phase of the cell cycle and inducing apoptosis in glioma cells. These data also provide a rationale for exploring the efficacy of HDAC inhibitors against gliomas and for developing tailored drug combinations that can exploit the changes induced by SAHA in gliomas.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]