Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases.
Disease progression in patients suffering from malignant melanomas is often determined by metastatic spreading into brain parenchyma. Systemic chemotherapy regimens are, therefore, mandatory for successful treatment. Most recently, inhibitors of histone deacetylases (HDACi) have been shown to significantly inhibit melanoma progression. Here, mouse as well as human melanoma cells were transplanted into rodent hippocampal slice cultures in order to translate and microscopically confirm promising in vitro chemotherapeutic propensities of HDACi within the organotypic brain environment. In our ex vivo model, tumor progression was significantly inhibited by administration of low micromolar concentrations of second generation HDACi MS-275 over a period of 8 days. In contrast, HDACi treatment with suberoylanilide hydroxamic acid was less efficient ex vivo, although both compounds were successful in the treatment of tumor cell monolayer cultures. Protein levels of the cell cycle inhibitor p21(WAF1) were significantly increased after HDACi treatment, which points to enhanced G1 arrest of tumor cells as confirmed by cytofluorometric analysis. Considering the ability of MS-275 to cross the blood-brain barrier, our experimental model identifies the benzamide MS-275 as a promising therapeutic compound for targeting epigenetic chromatin modulation as systemic treatment of metastatic melanomas.
Hölsken
Annett
A
Department of Neuropathology, University of Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054, Erlangen, Germany.
Eyüpoglu
Ilker Y
IY
Lueders
Mike
M
Tränkle
Christian
C
Dieckmann
Detlef
D
Buslei
Rolf
R
Hahnen
Eric
E
Blümcke
Ingmar
I
Siebzehnrübl
Florian A
FA
D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006624:Hippocampus; D056572:Histone Deacetylase Inhibitors; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D046509:Tissue Culture Techniques; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D001549:Benzamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; C118739:entinostat