HISTONE DEACETYLASE INHIBITOR PCI-24781 SHOWS ANTIPROLIFERATIVE EFFECTS AGAINST PEDIATRIC GLIOBLASTOMA CELLS

Abstract

BACKGROUND: Glioblastoma (GBM) is one of the most aggressive tumors affecting the central nervous system (CNS). Despite combined aggressive treatment schedules, the prognosis of children with GBM remains very poor. Epigenetic mechanisms may interfere with the process of carcinogenesis, and the acetylation of DNA can modulate the expression of genes related to the development and progression of malignancies. Clinical studies have shown that histone deacetylases inhibitors (HDACi are clinically active and well tolerated in the treatment of several tumors. Therefore, this study aims to evaluate the therapeutic potential of HDACi PCI-24781 in pediatric GBM lines, SF188 and KNS42 by proliferation assay. METHODS: Pediatric GMB cell-lines were cultured in HAM-F10 supplemented with 10% fetal bovine serum, at 37°C in a humidified 5% CO2 incubator. Cells were seeded in 96-well plates at 2x103 per well. After 24h, cells were treated with PCI-24781 at different concentrations (0.5, 1, 2, 4, 8 and 16 µM for 24, 48, 72 and 96h). Culture medium was removed and replaced with culture medium containing 5 µL of Resazurin dye in each well. Cells were incubated for 6h at 37°C, and the product was measured at 570 nm and 595 nm using a microplate reader. Statistical analysis was performed by One- and Two-way ANOVA and Bonferoni post-hoc. RESULTS: Both cell-lines were sensitive to PCI-24781 treatment, demonstrating an inhibition of proliferation (P < 0.05). For the SF188 cell-line, the strongest effect was observed at the doses of 4 µM, 8 µM and 16 µM at 96h (growth inhibition of 93%). The KNS42 cell-line showed a time-dependent antiproliferative pattern; the best effect was observed at 96h, when growth inhibition was of approximately 84%. It was observed time effect difference of proliferation between 24h and 48h (P < 0.05), but not between 48 h and 72 h. CONCLUSIONS: These primary data demonstrates that PCI-24781 can induce the inhibition of cell proliferation in pediatric GBM cells. Further experiments will be performed to assess the ability of this HDACi in modulating the cellular response in combinatin to ionizing radiation. Financial Support: FAPESP (process no. 2013/15891-8). SECONDARY CATEGORY: Preclinical Experimental Therapeutics.