Inhibition of 5-lipoxygenase pathway suppresses the growth of bladder cancer cells.
OBJECTIVE
Many stimuli, including growth factors and cytokines, activate arachidonic acid (AA) metabolic pathways, which are involved in cancer development and progression. We examined the effects of a series of pharmacological inhibitors of AA metabolic enzymes on bladder cancer cells to determine the role of AA pathway in this malignancy.


METHODS
Human bladder cancer cell lines were treated with various AA metabolic enzymes inhibitors for lipoxygense (LOX) and cyclooxygenase (COX) pathways, and the growth suppression effects were examined. The enzyme expression in cancer cells was examined by immunoblot analyses.


RESULTS
A 5-LOX-specific inhibitor, AA861, dose-dependently inhibited the growth of bladder cancer cells. The growth inhibitory effects were greatly abolished by 5-LOX product, 5-HETE, but not by other LOX products examined. They were observed in four cancer cells that expressed 5-LOX, but not in one that did not. Of a series of LOX and COX pathway inhibitors, AA861 was the strongest one to suppress the growth of cancer cells.


CONCLUSIONS
Bladder cancer cells frequently expressed 5-LOX. A 5-LOX-specific inhibitor, AA861, revealed the strongest growth suppression of those cells compared to other LOX and COX pathway inhibitors, and the growth suppression effects were considered to be due to inhibition of the enzymatic activity. Therefore, 5-LOX may play a regulatory role in proliferation and/or survival of bladder cancer, and may be a therapeutic target for the disease.
Hayashi
Toyohide
T
Department of Urology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan. tsushi@xd6.so-net.ne.jp
Nishiyama
Kenryu
K
Shirahama
Tsutomu
T
D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology / Q000502:physiology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology*
D016227:Benzoquinones; D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D001094:Arachidonate 5-Lipoxygenase