Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapenta
- PDF / 1,161,016 Bytes
- 12 Pages / 595.276 x 790.866 pts Page_size
- 95 Downloads / 186 Views
ORIGINAL ARTICLE
Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega‑3 polyunsaturated fatty acid eicosapentaenoic acid Milene Volpato1 · Nicola Ingram1 · Sarah L Perry1 · Jade Spencer2 · Amanda D Race2 · Catriona Marshall1 · John M Hutchinson1 · Anna Nicolaou3,4 · Paul M Loadman2 · P Louise Coletta1 · Mark A Hull1 Received: 15 June 2020 / Accepted: 24 September 2020 © The Author(s) 2020
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 drugnutrient interaction and careful tissue pharmacodynamic profiling is required in subsequent pre-clinical and human studies. Keywords Aspirin · Cancer pharmacology · Celecoxib · Colorectal cancer · Cyclooxygenase · Drug metabolism · Eicosapentaenoic acid
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04157-2) contains supplementary material, which is available to authorized users. * Milene Volpato [email protected] 1
Leeds Institute of Medical Research at St James’s, University of Leeds, St James’s University Hospital, Leeds LS9 7TF, UK
2
Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK
3
Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester M13 9PT, UK
4
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, UK
Omega-3 poly
Data Loading...
