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

World Journal of Surgical Oncology

Alexander M Seifalian²  Marc C Winslet²  Kevin Sales²  Daniel JB Marks¹  Radhakrishnan Ganesh² 

[1] Centre for Molecular Medicine, University College London, 5 University Street, London WC1E 6JF, UK;Division of Surgery and Interventional Science, University College London, Rowland Hill Street, London NW3 2PF, UK

关键词: Lipoxygenase;    Eicosanoids;    Cyclooxygenase;    Colorectal cancer;    Apoptosis;   

Others  :  827235
DOI  :  10.1186/1477-7819-10-200

 received in 2012-05-12, accepted in 2012-09-10,  发布年份 2012

【 摘 要 】

Background

Arachidonic 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.

Methods

Three 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.

Results

COX 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.

Conclusions

This 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.

【 授权许可】

   
2012 Ganesh et al.; licensee BioMed Central Ltd.

【 图 表 】

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