Overexpression of 5-Lipoxygenase in Colon Polyps and Cancer and the Effect of 5-LOX Inhibitors In vitro and in a Murine Model

Purpose: Arachidonic acid metabolism via the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways modulates cell growth and apoptosis. Many studies have examined the effects of COX inhibitors on human colorectal cancer, but the role of 5-LOX in colonic cancer development has not been well studie...

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Published in:Clinical cancer research 2008-10, Vol.14 (20), p.6525-6530
Main Authors: MELSTROM, Laleh G, BENTREM, David J, BELL, Richard H, ADRIAN, Thomas A, SALABAT, Mohammad R, KENNEDY, Timothy J, DING, Xian-Zhong, STROUCH, Matthew, RAO, Sambasiva M, WITT, Richard C, TERNENT, Charles A, TALAMONTI, Mark S
Format: Article
Language:English
Subjects:
5-lipoxygenase
5-LOX inhibitors
Adenoma - drug therapy
Adenoma - enzymology
Adenoma - pathology
Animals
Antineoplastic agents
Apoptosis - drug effects
Arachidonate 5-Lipoxygenase - metabolism
Biological and medical sciences
Cell Proliferation - drug effects
colon carcinoma
Colonic Neoplasms - drug therapy
Colonic Neoplasms - enzymology
Colonic Neoplasms - pathology
Colonic Polyps - drug therapy
Colonic Polyps - enzymology
Colonic Polyps - pathology
Disease Models, Animal
Female
Gastroenterology. Liver. Pancreas. Abdomen
growth inhibition
Humans
Immunoenzyme Techniques
In Vitro Techniques
Lipoxygenase Inhibitors - pharmacology
Masoprocol - therapeutic use
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Nude
Pharmacology. Drug treatments
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
RNA, Messenger - metabolism
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Thymidine - metabolism
Tumor Cells, Cultured
Tumors
Xenograft Model Antitumor Assays
zileuton
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Summary:Purpose: Arachidonic acid metabolism via the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways modulates cell growth and apoptosis. Many studies have examined the effects of COX inhibitors on human colorectal cancer, but the role of 5-LOX in colonic cancer development has not been well studied. The purpose of this study was to evaluate the expression of 5-LOX in colonic polyps and cancer and the effect of 5-LOX inhibition on colon cancer cell proliferation. Experimental Design: Colonic polyps, cancer, and normal mucosa were evaluated for 5-LOX expression by immunohistochemistry. Reverse transcription-PCR was used to establish 5-LOX expression in colon cancer cells. Thymidine incorporation and cell counts were used to determine the effect of the nonspecific LOX inhibitor Nordihydroguaiaretic Acid and the 5-LOX inhibitor Rev5901 on DNA synthesis. A heterotopic xenograft model in athymic mice using HT29 and LoVo human colon cancer cells was used to evaluate the effect of the 5-LOX inhibitor zileuton on tumor growth. Results: 5-LOX is overexpressed in adenomatous polyps and cancer compared with that of normal colonic mucosa. LOX inhibition and 5-LOX inhibition decreased DNA synthesis in a concentration- and time-dependent manner in the Lovo cell line ( P < 0.05). Inhibition of 5-LOX in an in vivo colon cancer xenograft model inhibited tumor growth compared with that of controls ( P < 0.05). Conclusions: This study showed that 5-LOX is up-regulated in adenomatous colon polyps and cancer compared with normal colonic mucosa. The blockade of 5-LOX inhibits colon cancer cell proliferation both in vitro and in vivo and may prove a beneficial chemopreventive therapy in colon cancer.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-07-4631