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

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.

RETRACTED: Association of Polyunsaturated Fatty Acid Intake on Inflammatory Gene Expression and Multiple Sclerosis: A Systematic Review and Meta-Analysis

“…The decreased levels of inflammatory eicosanoids such as leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) have been used to explain how omega-3 FAs have anti-inflammatory properties. Omega-FAs also control the activity of the enzymes cyclooxygenase (COX) and lipoxygenase (LOX) to modify the expression of anti-inflammatory eicosanoids and reduce the creation of inflammatory ones [ 70 ]. For instance, LTB4 is a powerful leukocyte chemoattractant made from arachidonic acid.…”

Omega-3 polyunsaturated fatty acids: moving towards precision use for prevention and treatment of colorectal cancer

“…These should include measurement of O3FA levels and parallel mechanistic studies, with which to confirm the validity of any hypothesis underlying post hoc analysis of RCT outcomes according to tumour biomarker stratification 13. A recent in vitro study reported that COX expression by human CRC cells was associated with relative resistance to EPA,90 an observation which is hard to reconcile with the CALGB 89803 finding that high O3FA intake was associated with larger CRC recurrence risk reduction in individuals with COX-2-high tumours 69…”

Bioactive lipids: Chemistry, biochemistry, and biological properties

“…(R. E. Gupta et al, 2012;Pimentel et al, 2013) EPA and DHA Anti-inflammatory effects through inhibition of nuclear factor kappa-B (NFκB) (Allam-Ndoul et al, 2016;Calder, 2013;Daak et al, 2015;Dang et al, 2017) 20 (Borghi & Cicero, 2006;Filipovic et al, 2018;Jayasooriya et al, 2008;Naini et al, 2015) Cancer EPA Anti-proliferative effects of cancer cells in colorectal cancer. By reducing the level of proinflammatory eicosanoids in prostate cells, the omega-3 PUFAs have the potential to limit cellular damage and reduce the risk for carcinogenesis (R. E. Aucoin et al, 2017;Volpato et al, 2020;C. D. Williams et al, 2011) 21 Sprat (≈17% fat)* 26-37 total PUFA → omega-3 PUFA 22-25.6 → 6.3 EPA+10 DHA (Keinänen et al, 2017;Regulska-Ilow et al, 2013) Salmon (10-13% fat)* 13.5-24.2 total PUFA; n-3 PUFA 0.53-2.4 (0.65 EPA+ 1.8 DHA) (Grahl-Nielsen & Glover, 2010;Linder et al, 2010;Strobel et al, 2012) Sardine (≈14% fat)* 30-49 total PUFA → n-3 PUFA 21-36 → 8.6-18.9 EPA+10.7-32.5 DHA (Bimbo, 2013;De Leonardis & Macciola, 2004;Shirai, 2011) Anchovy (8-16% fat)* 29.6-36 total PUFA → omega-3 PUFA 25.7-31.2 → 9.2-11.6 EPA+ 14.7-19 DHA (Kaya, 2008;ÖKsüz & Özyilmaz, 2010) Conjugated linoleic acid (CLA) Milk 0.7-1.03 total CLA → c9,t11 isomer 75-90% total CLA content (M. Guo, 2009;Kumar et al, 2018;Mushtaq et al, 2010;Rodríguez-Alcalá et al, 2017) Ruminant meat* 0.07-2.97 total CLA Cheese 0.06-1.42 total CLA → 0.14-0.73 c9,t11 isomer →78-84% total CLA content Conjugated linolenic acid (CLNA)…”