title: NBM-HD-3, a novel histone deacetylase inhibitor with anticancer activity through modulation of PTEN and AKT in brain cancer cells.
abstract: BACKGROUND
  Taiwanese green propolis (TGP) extract contains a variety of chemical components and has proven to have broad-spectrum biological activities, including anticancer, antioxidant, and antimicrobial activities. Propolin G, an active anticancer component of TGP, was isolated and characterized in this study. Histone deacetylase inhibitors (HDACis) have been shown to be effective anticancer agents. The aim of this study was to develop a novel HDACi and investigate its anticancer mechanism.
  
  
  METHODS
  NBM-HD-3, a novel HDACi, was derived from propolin G. Two brain cancer cell lines (c6 and DBTRG-05MG) were used in the anti-proliferation assay. NBM-HD-3 treated cells were analyzed by flow cytometry in the cell cycle assay. The gene expression of NBM-HD-3 treated cells was determined by real-time quantitative PCR. HDAC enzyme assay, confocal microscopy and Western blot assay were used to validate NMB-HD-3 as HDACi. Western blot assay was used for analyzing cell cycle modulation by PTEN and AKT.
  
  
  RESULTS
  NBM-HD-3 was found to have potent anti-proliferative activity in brain cancer cells (rat C6 glioma and human DBTRG-05MG glioblastoma). Western blot analysis and HDAC enzyme assay indicated that NBM-HD-3 was an HDAC inhibitor. The Western blot data exhibited increased levels of p21, Ac-histone 3, Ac-histone 4, and Ac-tubulin after brain cancer cells being treated with NBM-HD-3. NBM-HD-3 also affected the cell cycle regulators such as p21 and cyclin B1. In the study for its anticancer mechanism, NBM-HD-3 was found to increase PTEN and AKT protein levels significantly, while decreasing p-PTEN and p-AKT levels markedly.
  
  
  CONCLUSIONS
  This study demonstrated that the novel compound, NBM-HD-3, is a potent HDAC inhibitor. It produces anticancer activity through modulation of PTEN and AKT in brain cancer cells.
authors.affiliation: Graduate Institute of Pharmacognosy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Lin
authors.forename: Chi-Yun
authors.initials: CY
authors.lastname: Lee
authors.forename: Li-Ling
authors.initials: LL
authors.lastname: Chi
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Chao
authors.forename: Hsien-Ning
authors.initials: HN
authors.lastname: Wang
authors.forename: Bi-Lian
authors.initials: BL
authors.lastname: Chiou
authors.forename: Tzu-Jung
authors.initials: TJ
authors.lastname: Chen
authors.forename: Chung-Yang
authors.initials: CY
authors.lastname: Huang
authors.forename: Chia-Nan
authors.initials: CN
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D044950:Flavanones / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D039821:Monoterpenes / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011429:Propolis / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: C568902:6-(3-hydroxy-3-methylbutyl)-2'-(7-hydroxy-3,7-dimethyloct-3-enyl)-3',4',7-trimethoxyflavanone; D000970:Antineoplastic Agents; D003374:Coumarins; D004791:Enzyme Inhibitors; D044950:Flavanones; D039821:Monoterpenes; C524368:propolin G; D011429:Propolis; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D006655:Histone Deacetylases