Abstract
PurposeThe 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.MethodsA 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.ResultsGenetic 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.ConclusionCyclooxygenase 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.
Highlights
Omega-3 polyunsaturated fatty acid (O3FA) supplements containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are safe, well-tolerated, with beneficial cardiovascular effects [1, 2] and anti-inflammatory properties [3]
Human and mouse colorectal cancer (CRC) cell lines displayed a range of sensitivity to EPA in vitro, with IC50 values ranging from 38.0 ± 3.4 μM (MC38 mouse CRC cells) to 241.8 ± 1.1 μM
We examined a pair of isogenic mouse CRC cell lines; CT26, which is relatively resistant to EPA (Fig. 1), and COXlow-CT26, in which expression and activity of both COX isoforms are reduced by CRISPR/Cas9 editing [19], thereby providing a genetic model of dual, non-selective COX inhibition that is achieved by non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen
Summary
Omega-3 polyunsaturated fatty acid (O3FA) supplements containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are safe, well-tolerated, with beneficial cardiovascular effects [1, 2] and anti-inflammatory properties [3]. A phase 2 RCT of EPA 2 g FFA daily in patients awaiting liver resection surgery for CRCLM (the EMT trial) showed that EPA was safe and well-tolerated in advanced CRC patients [9]. Human CRC cells display differential sensitivity to EPA in vitro. Differential sensitivity to EPA is observed in other cancer cell types with 5–10 μM EPA reported to inhibit the growth of three human pancreatic cancer cell lines [14]. We exploited differential sensitivity of CRC cells to EPA to delineate factors controlling resistance to EPA, with a view to optimising anti-cancer treatment with this O3FA. We identified the COX isoforms as mediators of CRC cell resistance and tested the hypothesis that COX inhibition, which is a clinically relevant intervention using available non-steroidal anti-inflammatory drugs (NSAIDs), increases CRC cell sensitivity to the growth inhibitory effects of EPA
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