title: Synergistic effects of arsenic trioxide combined with ascorbic acid in human osteosarcoma MG-63 cells: a systems biology analysis.
abstract: OBJECTIVE
  To further understand the synergistic mechanism of As2O3 and asscorbic acid (AA) in human osteosarcoma MG-63 cells by systems biology analysis.
  
  
  METHODS
  Human osteosarcoma MG-63 cells were treated by As2O3 (1 µmol/L), AA (62.5 µmol/L) and combined drugs (1 µmol/L As2O3 plus 62.5 µmol/L AA). Dynamic morphological characteristics were recorded by Cell-IQ system, and growth rate was calculated. Illumina beadchip assay was used to analyze the differential expression genes in different groups. Synergic effects on differential expression genes (DEGs) were analyzed by mixture linear model and singular value decomposition model. KEGG pathway annotations and GO enrichment analysis were performed to figure out the pathways involved in the synergic effects.
  
  
  RESULTS
  We captured 1987 differential expression genes in combined therapy MG-63 cells. FAT1 gene was significantly upregulated in all three groups, which is a promising drug target as an important tumor suppressor analogue; meanwhile, HIST1H2BD gene was markedly downregulated in the As2O3 monotherapy group and the combined therapy group, which was found to be upregulated in prostatic cancer. These two genes might play critical roles in synergetic effects of AA and As2O3, although the exact mechanism needs further investigation. KEGG pathway analysis showed many DEGs were related with tight junction, and GO analysis also indicated that DEGs in the combined therapy cells gathered in occluding junction, apical junction complex, cell junction, and tight junction.
  
  
  CONCLUSIONS
  AA potentiates the efficacy of As2O3 in MG-63 cells. Systems biology analysis showed the synergic effect on the DEGs.
authors.affiliation: Rehabilitation Department, Zhongshan Hospital of Fudan University, Shanghai, China. zenggan@yahoo.com.
authors.forename: X C
authors.initials: XC
authors.lastname: Huang
authors.forename: X Y M
authors.initials: XY
authors.lastname: Maimaiti
authors.forename: C W
authors.initials: CW
authors.lastname: Huang
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: Z B
authors.initials: ZB
authors.lastname: Li
authors.forename: Z G
authors.initials: ZG
authors.lastname: Chen
authors.forename: X
authors.initials: X
authors.lastname: Gao
authors.forename: T Y
authors.initials: TY
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage*; D001205:Ascorbic Acid / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology; D010087:Oxides / Q000008:administration & dosage*; D049490:Systems Biology / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D001205:Ascorbic Acid; D000077237:Arsenic Trioxide