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

Clin Cancer Res. 2008 Oct 15;14(20):6525-30. doi: 10.1158/1078-0432.CCR-07-4631.

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.

Publication types

  • Comparative Study

MeSH terms

  • Adenoma / drug therapy
  • Adenoma / enzymology
  • Adenoma / pathology
  • Animals
  • Apoptosis / drug effects
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / enzymology*
  • Colonic Neoplasms / pathology
  • Colonic Polyps / drug therapy
  • Colonic Polyps / enzymology*
  • Colonic Polyps / pathology
  • Disease Models, Animal*
  • Female
  • Humans
  • Immunoenzyme Techniques
  • In Vitro Techniques
  • Lipoxygenase Inhibitors / pharmacology*
  • Masoprocol / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thymidine / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Lipoxygenase Inhibitors
  • RNA, Messenger
  • Masoprocol
  • Arachidonate 5-Lipoxygenase
  • Thymidine