title: Five-lipoxygenase-activating protein inhibitor MK-886 induces apoptosis in gastric cancer through upregulation of p27kip1 and bax.
abstract: OBJECTIVE
  Products of the arachidonic acid metabolizing enzyme, 5-lipoxygenase (5-LOX), stimulate the growth of several cancer types. Inhibitors of 5-LOX and 5-LOX-activating protein (FLAP) induce apoptosis in some cancer cells. Here, the authors investigated the effect of a FLAP inhibitor, MK-886, on the inhibition of proliferation and induction of apoptosis in gastric cancer.
  
  
  METHODS
  Cell proliferation in gastric cancer cells was measured using an 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Apoptosis was measured using acridine orange staining and flow cytometry. Protein expression of apoptosis-related genes p53, p21waf1, p27kip1, bcl-2 families, cytochrome c, and the caspases were examined using Western blotting. Caspase-3 activity was measured using colorimetric assay of substrate cleavage.
  
  
  RESULTS
  MK-886 inhibited cell growth in a dose- and time-dependent manner. Apoptosis was induced in gastric cancer cells and was characterized by upregulation of p27kip1 and bax, with release of cytochrome c from mitochondria into cytosol, which initiated caspase-3 activation. Specific caspase-3 inhibitors partially blocked MK-886-induced apoptosis.
  
  
  CONCLUSIONS
  The present results suggest that MK-886 induces apoptosis in gastric cancer cells through upregulation of p27kip1 and bax, and that MK-886 is a potentially useful drug in gastric cancer prevention and therapy.
authors.affiliation: Department of Medicine, Fudan University Affiliated Jinshan Hospital, Shanghai, China.
authors.forename: Xiao Ming
authors.initials: XM
authors.lastname: Fan
authors.forename: Shui Ping
authors.initials: SP
authors.lastname: Tu
authors.forename: Shiu Kum
authors.initials: SK
authors.lastname: Lam
authors.forename: Wei Ping
authors.initials: WP
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Wai Man
authors.initials: WM
authors.lastname: Wong
authors.forename: Man Fung
authors.initials: MF
authors.lastname: Yuen
authors.forename: Marie Chia Mi
authors.initials: MC
authors.lastname: Lin
authors.forename: Hsiange Fu
authors.initials: HF
authors.lastname: Kung
authors.forename: Benjamin Chun-Yu
authors.initials: BC
authors.lastname: Wong
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D045304:Cytochromes c / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D013274:Stomach Neoplasms / Q000276:immunology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein; D002722:Chlorobenzenes
chemical_list: D020169:Caspases; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D045304:Cytochromes c; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C060893:MK-886; D002722:Chlorobenzenes