apicidin and thiazolyl-blue

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 microm. 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.

Topics: Acetylation; Animals; Animals, Newborn; Antineoplastic Agents; Apoptosis; Benzamides; Blotting, Western; Cell Cycle Proteins; Cell Growth Processes; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Dose-Response Relationship, Drug; Flow Cytometry; Glioma; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Mice; Neoplasm Transplantation; Organ Culture Techniques; Peptides, Cyclic; Rats; Rats, Inbred F344; Rats, Wistar; Tetrazolium Salts; Thiazoles; Time Factors; Vorinostat