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Five‐lipoxygenase‐activating protein inhibitor MK‐886 induces apoptosis in gastric cancer through upregulation of p27 kip1 and bax
Author(s) -
FAN XIAO MING,
TU SHUI PING,
LAM SHIU KUM,
WANG WEI PING,
WU JING,
WONG WAI MAN,
YUEN MAN FUNG,
LIN MARIE CHIA MI,
KUNG HSIANG FU,
WONG BENJAMIN CHUNYU
Publication year - 2004
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/j.1440-1746.2004.03194.x
Subject(s) - apoptosis , cancer cell , cytochrome c , downregulation and upregulation , caspase , microbiology and biotechnology , cancer research , acridine orange , biology , cancer , programmed cell death , biochemistry , genetics , gene
Abstract Background and Aim: 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, p21 waf1 , p27 kip1 , 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 p27 kip1 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. Conclusion: The present results suggest that MK‐886 induces apoptosis in gastric cancer cells through upregulation of p27 kip1 and bax, and that MK‐886 is a potentially useful drug in gastric cancer prevention and therapy.