Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid
| Autor: | Milene Volpato, John Hutchinson, Catriona Marshall, P. Louise Coletta, Jade A. Spencer, Nicola Ingram, SL Perry, Anna Nicolaou, Paul M. Loadman, Mark A. Hull, Amanda D. Race |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Cell Toxicology Mice chemistry.chemical_compound 0302 clinical medicine Cancer pharmacology Pharmacology (medical) chemistry.chemical_classification Mice Inbred BALB C Aspirin biology Anti-Inflammatory Agents Non-Steroidal Eicosapentaenoic acid Cyclooxygenase medicine.anatomical_structure Eicosapentaenoic Acid Oncology 030220 oncology & carcinogenesis Original Article lipids (amino acids peptides and proteins) Female Growth inhibition Colorectal Neoplasms medicine.drug Polyunsaturated fatty acid Mice Nude Antineoplastic Agents 03 medical and health sciences In vivo Cell Line Tumor medicine Animals Humans Cyclooxygenase Inhibitors Pharmacology Drug metabolism Cyclooxygenase 2 Inhibitors Correction Colorectal cancer Xenograft Model Antitumor Assays 030104 developmental biology chemistry Celecoxib Drug Resistance Neoplasm Cell culture Cancer research biology.protein |
| Zdroj: | Nicolaou, A & et al. 2020, ' Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid ', Cancer Chemotherapy and Pharmacology . https://doi.org/10.1007/s00280-020-04157-2 Cancer Chemother Pharmacol Cancer Chemotherapy and Pharmacology |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s00280-020-04157-2 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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