Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275.
Inhibitors of histone deacetylases are promising compounds for the treatment of cancer but have not been systematically explored in malignant brain tumors. Here, we characterize the benzamide MS-275, a class I histone deacetylase inhibitor, as potent drug for experimental therapy of glioblastomas. Treatment of four glioma cell lines (U87MG, C6, F98, and SMA-560) with MS-275 significantly reduced cell growth in a concentration-dependent manner (IC(90), 3.75 micromol/L). Its antiproliferative effect was corroborated using a bromodeoxyuridine proliferation assay and was mediated by G(0)-G(1) cell cycle arrest (i.e., up-regulation of p21/WAF) and apoptotic cell death. Implantation of enhanced green fluorescent protein-transfected F98 glioma cells into slice cultures of rat brain confirmed the cytostatic effect of MS-275 without neurotoxic damage to the organotypic neuronal environment in a dose escalation up to 20 micromol/L. A single intratumoral injection of MS-275 7 days after orthotopic implantation of glioma cells in syngeneic rats confirmed the chemotherapeutic efficacy of MS-275 in vivo. Furthermore, its propensity to pass the blood-brain barrier and to increase the protein level of acetylated histone H3 in brain tissue identifies MS-275 as a promising candidate drug in the treatment of malignant gliomas.
Eyüpoglu
Ilker Y
IY
Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. eyupoglu@gmx.net
Hahnen
Eric
E
Tränkle
Christian
C
Savaskan
Nicolai E
NE
Siebzehnrübl
Florian A
FA
Buslei
Rolf
R
Lemke
Dieter
D
Wick
Wolfgang
W
Fahlbusch
Rudolf
R
Blümcke
Ingmar
I
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001549:Benzamides / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D000077204:Temozolomide; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; D015816:Cell Adhesion Molecules, Neuronal; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; C118739:entinostat; D003606:Dacarbazine; D006655:Histone Deacetylases; D000077204:Temozolomide