title: Chemosensitization of glioblastoma cells by the histone deacetylase inhibitor MS275.
abstract: Glioblastoma is the most common primary brain tumor with a dismal prognosis, highlighting the need for novel treatment strategies. Here, we provide the first evidence that the histone deacetylase inhibitor, MS275, sensitizes glioblastoma cells for chemotherapy-induced apoptosis. Pretreatment of glioblastoma cells with MS275 causes acetylation of histone H3 protein and significantly enhances doxorubicin-induced apoptosis. Calculation of combination index showed that MS275 and doxorubicin acted in a synergistic manner to trigger apoptosis. Furthermore, pre-exposure to MS275 significantly increases apoptosis in response to temozolomide, etoposide, and cisplatin. In contrast, treatment with MS275 before the addition of vincristine and taxol significantly reduces the induction of apoptosis. Analysis of cell cycle alterations showed that treatment with MS275 triggers G1 cell cycle arrest, which in turn renders cells less sensitive to the cytotoxic effects of mitotic inhibitors, such as vincristine and taxol. Thus, these findings show for the first time that the histone deacetylase inhibitor, MS275, represents a promising strategy to prime glioblastoma cells for chemotherapy-induced apoptosis in a drug-specific manner.
authors.affiliation: University Children's Hospital, Ulm, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Bangert
authors.forename: Sabine
authors.initials: S
authors.lastname: Häcker
authors.forename: Silvia
authors.initials: S
authors.lastname: Cristofanon
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D002945:Cisplatin / Q000494:pharmacology; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D000077204:Temozolomide
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011725:Pyridines; C118739:entinostat; D005047:Etoposide; D003606:Dacarbazine; D004317:Doxorubicin; D002945:Cisplatin; D000077204:Temozolomide