title: Zebularine inhibits the growth of A549 lung cancer cells via cell cycle arrest and apoptosis.
abstract: Zebularine (Zeb) is a DNA methyltransferase (DNMT) inhibitor to that has an anti-tumor effect. Here, we evaluated the anti-growth effect of Zeb on A549 lung cancer cells in relation to reactive oxygen species (ROS) levels. Zeb inhibited the growth of A549 cells with an IC50 of approximately 70 µM at 72 h. Cell cycle analysis indicated that Zeb induced an S phase arrest in A549 cells. Zeb also induced A549 cell death, which was accompanied by the loss of mitochondrial membrane potential (MMP; ΔΨm ), Bcl-2 decrease, Bax increase, p53 increase and activation of caspase-3 and -8. In contrast, Zeb mildly inhibited the growth of human pulmonary fibroblast (HPF) normal cells and lead to a G1 phase arrest. Zeb did not induce apoptosis in HPF cells. In relation to ROS level, Zeb increased ROS level in A549 cells and induced glutathione (GSH) depletion. The well-known antioxidant, N-acetyl cysteine (NAC) prevented the death of Zeb-treated A549 cells. Moreover, Zeb increased the level of thioredoxin reductase 1 (TrxR1) in A549 cells. While the overexpression of TrxR1 attenuated death and ROS level in Zeb-treated A549 cells, the downregulation of TrxR1 intensified death and ROS level in these cells. In conclusion, Zeb inhibited the growth of A549 lung cancer cells via cell cycle arrest and apoptosis. The inhibition was influenced by ROS and TrxR1 levels.
authors: Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, Jeonju, Republic of Korea.
authors: Bo Ra
authors: BR
authors: You
authors: Woo Hyun
authors: WH
authors: Park
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000096:biosynthesis; D053181:Caspase 8 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D054481:Thioredoxin Reductase 1 / Q000096:biosynthesis* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D000975:Antioxidants; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D015254:DNA Modification Methylases; D053148:Caspase 3; D053181:Caspase 8; D005978:Glutathione; D000111:Acetylcysteine
keywords: A549; DNA methyltransferase; apoptosis; thioredoxin reductase; zebularine