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

• Published in: Journal of neurochemistry Vol. 93; no. 4; pp. 992 - 999
• Main Authors: Eyüpoglu, Ilker Y., Hahnen, Eric, Buslei, Rolf, Siebzehnrübl, Florian A., Savaskan, Nicolai E., Lüders, Mike, Tränkle, Christian, Wick, Wolfgang, Weller, Michael, Fahlbusch, Rudolf, Blümcke, Ingmar
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.05.2005; Blackwell
• Subjects: Acetylation - drug effects; Animals; Animals, Newborn; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Benzamides - therapeutic use; Biological and medical sciences; Blotting, Western - methods; Cell Cycle Proteins - metabolism; Cell Growth Processes - drug effects; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Dose-Response Relationship, Drug; drug; Flow Cytometry - methods; Fundamental and applied biological sciences. Psychology; glioblastoma; Glioma - drug therapy; Glioma - metabolism; Glioma - pathology; Histone Deacetylase Inhibitors; histone deacetylases; Histones - metabolism; Humans; Hydroxamic Acids - therapeutic use; Isolated neuron and nerve. Neuroglia; Medical sciences; Mice; Neoplasm Transplantation - methods; Neurology; Organ Culture Techniques; Peptides, Cyclic - therapeutic use; Rats; Rats, Inbred F344; Rats, Wistar; slice culture; Tetrazolium Salts; Thiazoles; Time Factors; treatment; Tumors of the nervous system. Phacomatoses; tumour; Vertebrates: nervous system and sense organs; Rat; Growth; Central nervous system; Glioblastoma; drug; Malignant glioma; Regulation(control); tumour; Cell cycle; histone deacetylases; Histone; slice culture; Human; Nervous system diseases; Induction; Rodentia; Malignant tumor; In vitro; Long term; Survival; Protein; Vertebrata; Mammalia; Cell line; Treatment; Mouse; Central nervous system disease
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03098.x

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.