Molecular and cellular effects of a novel hydroxamate-based HDAC inhibitor – belinostat – in glioblastoma cell lines: a preliminary report

• DOI: 10.1007/s10637-016-0372-5
• Publication Date: 2016-07-29T02:21:12Z
• Authors: Magdalena Kusaczuk; Rafał Krętowski; Anna Stypułkowska; Marzanna Cechowsk...
• Keywords: Pharmacology; Cyclin-Dependent Kinase Inhibitor p21; 0301 basic medicine; Preclinical Studies; Sulfonamides; Bcl-2-Like Protein 11; Cell Survival; Antineoplastic Agents; Apoptosis; Hydroxamic Acids; Histone Deacetylases; 3. Good health; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; 03 medical and health sciences; Oncology; Cell Line, Tumor; Proto-Oncogene Proteins; Humans; Pharmacology (medical); Apoptosis Regulatory Proteins; Glioblastoma; Endoplasmic Reticulum Chaperone BiP; Transcription Factor CHOP

SummaryHistone deacetylase (HDAC) inhibitors are now intensively investigated as potential cytostatic agents in many malignancies. Here, we provide novel information concerning the influence of belinostat (Bel), a hydroxamate-based pan-HDAC inhibitor, on glioblastoma LN-229 and LN-18 cells. We found that LN-229 cells stimulated with 2 μmol/L of Bel for 48 h resulted in 70 % apoptosis, while equivalent treatment of LN-18 cells resulted in only 28 % apoptosis. In LN-229 cells this effect was followed by up-regulation of pro-apoptotic genes including Puma, Bim, Chop and p21. In treated LN-18 cells only p21 was markedly overexpressed. Simultaneously, LN-229 cells treated with 2 μmol/L of Bel for 48 h exhibited down-regulation of molecular chaperones GRP78 and GRP94 at the protein level. In contrast, in LN-18 cells Western blot analysis did not show any marked changes in GRP78 nor GRP94 expression. Despite noticeable overexpression of p21, there were no signs of evident G1 nor G2/M cell cycle arrest, however, the reduction in number of the S phase cells was observed in both cell lines. These results collectively suggest that Bel can be considered as potential anti-glioblastoma agent. To our knowledge this is the first report presenting the effects of belinostat treatment in glioblastoma cell lines.