Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo

Authors


Address correspondence and reprint requests to I. Y. Eyüpoglu MD, Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.
E-mail: eyupoglu@gmx.net

Abstract

Current treatment modalities for malignant gliomas do not allow long-term survival. Here, we identify suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylases (HDAC), as an effective experimental anti-glioma agent. Administration of SAHA to various glioma cell lines obtained from human, rat and mouse inhibited tumour cell growth in a range of 1–10 μm. This anti-glioma property is associated with up-regulation of the cell cycle control protein p21/WAF, as well as the induction of apoptosis. A novel tumour invasion model using slice cultures of rat brain corroborated the anti-glioma properties of SAHA in the organotypic brain environment. In this model, glioma invasion compromised adjacent brain parenchyma, and this tumour-associated cytotoxicity could be inhibited by SAHA. In addition, a 10-fold dose escalation experiment did not challenge the viability of cultured brain slices. In vivo, a single intratumoural injection of SAHA 7 days after orthotopic implantation of glioma cells in syngeneic rats doubled their survival time. These observations identify chromatin-modifying enzymes as possible and promising targets for the pharmacotherapy of malignant gliomas.

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