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World Journal of Surgical Oncology

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Open Access 01-12-2012 | Research

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

Authors: Radhakrishnan Ganesh, Daniel JB Marks, Kevin Sales, Marc C Winslet, Alexander M Seifalian

Published in: World Journal of Surgical Oncology | Issue 1/2012

Abstract

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.

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Title: Cyclooxygenase/lipoxygenase shunting lowers the anti-cancer effect of cyclooxygenase-2 inhibition in colorectal cancer cells
Authors: Radhakrishnan Ganesh
Daniel JB Marks
Kevin Sales
Marc C Winslet
Alexander M Seifalian
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: World Journal of Surgical Oncology / Issue 1/2012
Electronic ISSN: 1477-7819
DOI: https://doi.org/10.1186/1477-7819-10-200

ACC 2024 Congress

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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