Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo.
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.
Eyüpoglu
Ilker Y
IY
Department of Neurosurgery, University of Erlangen, Germany. eyupoglu@gmx.net
Hahnen
Eric
E
Buslei
Rolf
R
Siebzehnrübl
Florian A
FA
Savaskan
Nicolai E
NE
Lüders
Mike
M
Tränkle
Christian
C
Wick
Wolfgang
W
Weller
Michael
M
Fahlbusch
Rudolf
R
Blümcke
Ingmar
I
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000627:therapeutic use; D015153:Blotting, Western / Q000379:methods; D018797:Cell Cycle Proteins / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry / Q000379:methods; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D051379:Mice; D009368:Neoplasm Transplantation / Q000379:methods; D009924:Organ Culture Techniques; D010456:Peptides, Cyclic / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D000077337:Vorinostat
D000970:Antineoplastic Agents; D001549:Benzamides; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D010456:Peptides, Cyclic; D013778:Tetrazolium Salts; D013844:Thiazoles; C102351:apicidin; D000077337:Vorinostat; C022616:thiazolyl blue