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Open Access 01-02-2021 | Celecoxib | Original Article

Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid

Authors: Milene Volpato, Nicola Ingram, Sarah L Perry, Jade Spencer, Amanda D Race, Catriona Marshall, John M Hutchinson, Anna Nicolaou, Paul M Loadman, P Louise Coletta, Mark A Hull

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2021

Abstract

Purpose

The naturally-occurring omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and inexpensive, making it an attractive anti-cancer intervention. However, EPA has only modest anti-colorectal cancer (CRC) activity, when used alone. Both cyclooxygenase (COX) isoforms metabolise EPA and are over-expressed in CRC cells. We investigated whether COX inhibition increases the sensitivity of CRC cells to growth inhibition by EPA.

Methods

A panel of 18 human and mouse CRC cell lines was used to characterize the differential sensitivity of CRC cells to the growth inhibitory effects of EPA. The effect of CRISPR-Cas9 genetic deletion and pharmacological inhibition of COX-1 and COX-2 on the anti-cancer activity of EPA was determined using in vitro and in vivo models.

Results

Genetic ablation of both COX isoforms increased sensitivity of CT26 mouse CRC cells to growth inhibition by EPA in vitro and in vivo. The non-selective COX inhibitor aspirin and the selective COX-2 inhibitor celecoxib increased sensitivity of several human and mouse CRC cell lines to EPA in vitro. However, in a MC38 mouse CRC cell tumour model, with dosing that mirrored low-dose aspirin use in humans, thereby producing significant platelet COX-1 inhibition, there was ineffective intra-tumoral COX-2 inhibition by aspirin and no effect on EPA sensitivity of MC38 cell tumours.

Conclusion

Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs represents a therapeutic opportunity to augment the modest anti-CRC activity of EPA. However, intra-tumoral COX inhibition is likely to be critical for this drug-nutrient interaction and careful tissue pharmacodynamic profiling is required in subsequent pre-clinical and human studies.

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Title: Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid
Authors: Milene Volpato
Nicola Ingram
Sarah L Perry
Jade Spencer
Amanda D Race
Catriona Marshall
John M Hutchinson
Anna Nicolaou
Paul M Loadman
P Louise Coletta
Mark A Hull
Publication date: 01-02-2021
Publisher: Springer Berlin Heidelberg
Keywords: Celecoxib
Colorectal Cancer
Colorectal Cancer
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2021
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04157-2

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