title: Antiproliferative and proapoptotic effects of histone deacetylase inhibitors on gastrointestinal neuroendocrine tumor cells.
abstract: Treatment options of advanced neuroendocrine tumors (NETs) are unsatisfactory. Hence, innovative therapeutic approaches are urgently needed. Inhibition of histone deacetylases (HDACs) is a promising new approach in cancer therapy. While several HDAC inhibitors have already entered clinical trials, the effect of HDAC inhibition on NET has not been investigated. Therefore, we evaluated the antineoplastic effects of three different HDAC inhibitors, trichostatin A (TSA), sodium butyrate (NaB), and MS-275, on growth and apoptosis of the gastrointestinal NET cell lines CM and BON. We could demonstrate that HDAC inhibition dose-dependently inhibited proliferation of both cell lines with IC50 values varying from the millimolar (NaB) to the micromolar (MS-275) and the nanomolar range (TSA). Moreover, HDAC inhibition potently induced apoptosis, which was accompanied by DNA-fragmentation, an up to 12-fold caspase-3 activation and downregulated Bcl-2 expression. Furthermore, HDAC inhibition resulted in cell cycle arrest at the G1-S-transition, which was associated with the suppression of cyclin D1 expression and induction of p21 and p27 expression. For BON cells, we observed an additional block in the G2/M phase, which was aligned with a downregulation of cyclin B1. In addition, combined treatment with MS-275 and somatostatin or the synthetic somatostatin analog octreotide was evaluated. Neither somatostatin nor its stable analog octreotide augmented the antiproliferative effect of MS-275 in NET cells. To conclude, our data show that HDAC inhibition is a promising new approach in the treatment of NET disease, which should be evaluated in clinical studies.
authors.affiliation: Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Viola
authors.initials: V
authors.lastname: Baradari
authors.forename: Alexander
authors.initials: A
authors.lastname: Huether
authors.forename: Michael
authors.initials: M
authors.lastname: Höpfner
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: Hans
authors.initials: H
authors.lastname: Scherübl
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D002276:Carcinoid Tumor / Q000188:drug therapy / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D019938:Cyclin D1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000378:metabolism; D015282:Octreotide / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013004:Somatostatin / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D002087:Butyrates; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006728:Hormones; D006877:Hydroxamic Acids; D011725:Pyridines; D019938:Cyclin D1; C118739:entinostat; C012589:trichostatin A; D013004:Somatostatin; D020169:Caspases; D015282:Octreotide