Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega‑3 polyunsaturated fatty acid eicosapentaenoic acid
Volpato, M. Ingram, N. Perry, S.L. Spencer, Jade Race, Amanda D. Marshall, C. Hutchinson, J.M. Nicolaou, A. Coletta, P.L.
Volpato, M.
Ingram, N.
Perry, S.L.
Spencer, Jade
Race, Amanda D.
Marshall, C.
Hutchinson, J.M.
Nicolaou, A.
Coletta, P.L.
Publication Date
2020-09-11
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© 2020 The Authors. Published by Springer. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material.
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openAccess
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2020-09-24
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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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Citation
Volpato M, Ingram N, Perry SL, et al (2020) Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega‑3 polyunsaturated fatty acid eicosapentaenoic acid. Cancer chemotherapy and pharmacology. 87: 173–184
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Article