Cyclooxygenase/lipoxygenase shunting lowers the anti-cancer effect of cyclooxygenase-2 inhibition in colorectal cancer cells

Abstract

BackgroundArachidonic acid metabolite, generated by cyclooxygenase (COX), is implicated in the colorectal cancer (CRC) pathogenesis. Inhibiting COX may therefore have anti-carcinogenic effects. Results from use of non-steroidal anti-inflammatory drugs inhibiting only COX have been conflicting. It has been postulated that this might result from the shunting of arachidonic acid metabolism to the 5-lipoxygenase (5-LOX) pathway. Cancer cell viability is promoted by 5-LOX through several mechanisms that are similar to those of cyclooxygenase-2 (COX-2). Expression of 5-LOX is upregulated in colorectal adenoma and cancer. The aim of this study was to investigate the shunting of arachidonic acid metabolism to the 5-LOX pathway by cyclooxygenase inhibition and to determine if this process antagonizes the anti-cancer effect in colorectal cancer cells.MethodsThree colorectal cancer cell lines (HCA7, HT-29 & LoVo) expressing 5-LOX and different levels of COX-2 expression were used. The effects of aspirin (a non-selective COX inhibitor) and rofecoxib (COX-2 selective) on prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) secretion were quantified by ELISA. Proliferation and viability were studied by quantifying double-stranded DNA (dsDNA) content and metabolic activity. Apoptosis was determined by annexin V and propidium iodide staining using confocal microscopy, and caspase-3/7 activity by fluorescent substrate assay.ResultsCOX inhibitors suppressed PGE2 production but enhanced LTB4 secretion in COX-2 expressing cell lines (P <0.001). The level of COX-2 expression in colorectal cancer cells did not significantly influence the anti-proliferative and pro-apoptotic effects of COX inhibitors due to the shunting mechanism.ConclusionsThis study provides evidence of shunting between COX and 5-LOX pathways in the presence of unilateral inhibition, and may explain the conflicting anti-carcinogenic effects reported with use of COX inhibitors.

Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment

“…Furthermore, our eicosanoid profiling indicates that tumor bearing lungs in 5-LO-KO mice have modestly increased levels of COX products. Previous reports have shown competition between COX and 5-LO for substrate, leading to shunting of arachidonic acid into 5-LO pathways in the setting of COX inhibitors (35). We would propose that in cells of the tumor microenvironment, the loss of 5-LO expression as occurs in the 5-LO-KO mice results in greater availability of arachidonic acid for COX pathways, leading to the observed increases in prostaglandin production, which could contribute to increased cancer progression in the setting of 5-LO knockout.…”

Molecular targeted therapy for the treatment of gastric cancer

“…COX-2 is involved in tumorigenesis and cancer development via the promotion of cell proliferation, suppression of apoptosis, and induction of tumor angiogenesis. COX-2 inhibitors have been demonstrated to exert anti-cancer effects on gastric cancer cells; however, precise clinical trial data are lacking [ 76 ]. Importantly, the gastrointestinal adverse effects of COX inhibitors limit their widespread clinical application.…”

Radioprotective effect of mefenamic acid against radiation-induced genotoxicity in human lymphocytes

“…Different mechanisms are proposed for anti-cancer effect of MEF to be caspase-3 pathway and inhibiting of the synthesis of hyaluronic acid and cyclooxygenase [ 18 19 20 21 ]. COX-2 is frequently over expressed in various cancer tissues, thus inhibition of COX-2 by NSAID is suggested as a strategy for cancer treatment and prevention [ 20 21 22 23 24 ]. While inflammatory environment is linked to DNA damage and death in normal cells, proinflammatory cytokines are involved in cancer cell growth [ 25 26 ].…”