Overexpression of 5-lipoxygenase in colon polyps and cancer and the effect of 5-LOX Inhibitors in vitro and in a murine model

Laleh G. Melstrom, David J. Bentrem, Mohammad R. Salabat, Timothy J. Kennedy, Xian Zhong Ding, Matthew Strouch, Sambasiva M. Rao, Richard C. Witt, Charles A. Ternent, Mark S. Talamonti, Richard H. Bell, Thomas A. Adrian

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)6525-6530
Number of pages6
JournalClinical Cancer Research
Volume14
Issue number20
DOIs
StatePublished - Oct 15 2008

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Melstrom, L. G., Bentrem, D. J., Salabat, M. R., Kennedy, T. J., Ding, X. Z., Strouch, M., Rao, S. M., Witt, R. C., Ternent, C. A., Talamonti, M. S., Bell, R. H., & Adrian, T. A. (2008). Overexpression of 5-lipoxygenase in colon polyps and cancer and the effect of 5-LOX Inhibitors in vitro and in a murine model. Clinical Cancer Research, 14(20), 6525-6530. https://doi.org/10.1158/1078-0432.CCR-07-4631