title: Identification of novel DNA methylation inhibitors via a two-component reporter gene system.
abstract: BACKGROUND
  Targeting abnormal DNA methylation represents a therapeutically relevant strategy for cancer treatment as demonstrated by the US Food and Drug Administration approval of the DNA methyltransferase inhibitors azacytidine and 5-aza-2'-deoxycytidine for the treatment of myelodysplastic syndromes. But their use is associated with increased incidences of bone marrow suppression. Alternatively, procainamide has emerged as a potential DNA demethylating agent for clinical translation. While procainamide is much safer than 5-aza-2'-deoxycytidine, it requires high concentrations to be effective in DNA demethylation in suppressing cancer cell growth. Thus, our laboratories have embarked on the pharmacological exploitation of procainamide to develop potent DNA methylation inhibitors through lead optimization.
  
  
  METHODS
  We report the use of a DNA methylation two-component enhanced green fluorescent protein reporter system as a screening platform to identify novel DNA methylation inhibitors from a compound library containing procainamide derivatives.
  
  
  RESULTS
  A lead agent IM25, which exhibits substantially higher potency in GSTp1 DNA demethylation with lower cytotoxicity in MCF7 cells relative to procainamide and 5-aza-2'-deoxycytidine, was identified by the screening platform.
  
  
  CONCLUSIONS
  Our data provide a proof-of-concept that procainamide could be pharmacologically exploited to develop novel DNA methylation inhibitors, of which the translational potential in cancer therapy/prevention is currently under investigation.
authors.affiliation: Human Epigenomics Center, Department of Life Science, Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, 621, Taiwan.
authors.forename: Yi-Shiuan
authors.initials: YS
authors.lastname: Lin
authors.forename: Arthur Y
authors.initials: AY
authors.lastname: Shaw
authors.forename: Shi-Gang
authors.initials: SG
authors.lastname: Wang
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Hsu
authors.forename: I-Wen
authors.initials: IW
authors.lastname: Teng
authors.forename: Min-Jen
authors.initials: MJ
authors.lastname: Tseng
authors.forename: Tim H M
authors.initials: TH
authors.lastname: Huang
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Leu
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Hsiao
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000378:metabolism*; D011342:Procainamide / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D000964:Antimetabolites, Antineoplastic; D011342:Procainamide