binations of DNA Methyltransferase and Histone cetylase Inhibitors Induce DNA Damage in Small l Lung Cancer Cells: Correlation of Resistance with

ownload ause epigenetic inhibitors can reduce cancer cell proliferation, we tested the hypothesis that concurrent tion of histone acetylation and DNA methylation could synergistically reduce the viability of small cell ancer (SCLC) cells. Sub-IC50 concentrations of the DNA methyltransferase (DNMT) inhibitor decitabine A-dC) and the histone deacetylase (HDAC) inhibitors (LBH589 or MGCD0103) synergistically reduced oliferation of five of nine SCLC cell lines. Loss of viability of sensitive SCLC cells did not correlate he inhibition of either DNMT1 or HDACs, suggesting nonepigenetic mechanisms for synergy between two classes of epigenetic modulators. Because combinations of 5-AZA-dC and HDAC inhibitors had nal effects on the apoptosis index, Comet assay was undertaken to assess DNA damage. MGCD0103 AZA-dC cotreatment augmented DNA damage in SCLC cells, resulting in increased tail length and nt in Comet assays by 24 hours in sensitive cell lines (P < 0.01). Consistent with augmented DNA e, combination of a DNMT and HDAC inhibitor markedly increased the levels of phospho-H2A.X sitive cells but not in resistant ones. Comparison of basal gene expression between resistant and ve cells identified markedly higher basal expression of IFN-stimulated genes in the resistant cell lines, sensiti suggesting that IFN-stimulated gene expression may determine SCLC cell sensitivity to epigenetic modulators or other DNA damaging agents. Mol Cancer Ther; 9(8); 2309–21. ©2010 AACR.