title: Azacitidine and decitabine have different mechanisms of action in non-small cell lung cancer cell lines.
abstract: Azacitidine (AZA) and decitabine (DAC) are cytidine azanucleoside analogs with clinical activity in myelodysplastic syndromes (MDS) and potential activity in solid tumors. To better understand the mechanism of action of these drugs, we examined the effects of AZA and DAC in a panel of non-small cell lung cancer (NSCLC) cell lines. Of 5 NSCLC lines tested in a cell viability assay, all were sensitive to AZA (EC50of 1.8-10.5 µM), while only H1299 cells were equally sensitive to DAC (EC50of 5.1 µM). In the relatively DAC-insensitive cell line A549, both AZA and DAC caused DNA methyltransferase I depletion and DNA hypomethylation; however, only AZA significantly induced markers of DNA damage and apoptosis, suggesting that mechanisms in addition to, or other than, DNA hypomethylation are important for AZA-induced cell death. Cell cycle analysis indicated that AZA induced an accumulation of cells in sub-G1 phase, whereas DAC mainly caused an increase of cells in G2/M. Gene expression analysis of AZA- and DAC-treated cells revealed strikingly different profiles, with many genes distinctly regulated by each drug. In summary, while both AZA and DAC caused DNA hypomethylation, distinct effects were demonstrated on regulation of gene expression, cell cycle, DNA damage, and apoptosis.
authors.affiliation: Celgene Corporation, San Francisco, CA, USA.
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Nguyen
authors.affiliation: Celgene Corporation, San Francisco, CA, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hollenbach
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Normand
authors.initials: N
authors.lastname: Richard
authors.affiliation: Celgene Corporation, San Francisco, CA, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Luna-Moran
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Brady
authors.affiliation: Celgene Corporation, San Francisco, CA, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Heise
authors.affiliation: Celgene Corporation, San Francisco, CA, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: MacBeth
keywords: apoptosis; azacitidine; decitabine; gene expression; non-small cell lung cancer