Electrophilic derivatives of omega-3 fatty acids counteract lung cancer cell growth
- 155 Downloads
17-oxo-DHA is an electrophilic keto-derivative of the omega-3 fatty acid docosahexaenoic acid (DHA) endogenously generated by cyclooxygenase-2 and a cellular dehydrogenase. 17-oxo-DHA displays anti-inflammatory and cytoprotective actions. DHA, alone or in combination with standard chemotherapy, displays antitumor activity. However, the effects of electrophilic keto-derivatives of DHA on cancer growth have never been evaluated. We investigated whether 17-oxo-DHA, alone or in combination with gemcitabine, displayed antitumor effects. Furthermore, we evaluated whether the enzyme 15-prostaglandin dehydrogenase (15-PGDH) was required for transducing the antitumor effects of DHA.
A panel of five histologically different human non-small cell lung cancer (NSCLC) cell lines was used. Cells were treated with 17-oxo-DHA and gemcitabine, alone or in combination, and apoptosis, proliferation, Fas and FasL expression (mRNA and protein) and active caspase-3/7 and -8 were assessed. Furthermore, an inhibitor of 15-PGDH was used to test the involvement of this enzyme in mediating the antitumor effects of DHA.
17-oxo-DHA (50 µM, 72 h) significantly reduced proliferation, increased cell apoptosis, Fas and FasL expression as well as active caspase-8 and -3/7. When 17-oxo-DHA was given in combination with gemcitabine, stronger effects were observed compared to gemcitabine alone. The enzyme 15-PGDH was required for DHA to promote its full anti-apoptotic effect suggesting that enzymatically generated keto-derivatives of DHA mediate its antitumor actions.
Data herein provided, demonstrate that 17-oxo-DHA displays antitumor effects in NSCLC cell lines. Of note, the combination of 17-oxo-DHA plus gemcitabine, resulted in stronger anticancer effects compared to gemcitabine alone.
KeywordsLung cancer Apoptosis Anti-cancer drugs Gemcitabine Combination therapy Electrophilic lipids Omega-3 polyunsaturated fatty acids 15-hydroxyprostaglandin dehydrogenase Fas Fas Ligand Caspases
Non-small cell lung cancer
- n-3 PUFAs
Omega-3 polyunsaturated fatty acids
Liboria Siena designed the study and performed the majority of the experiments. Liboria Siena suddenly died on November 2, 2016. Chiara Cipollina contributed to study design, performed the experiments, contributed to data interpretation and manuscript writing. Serena Di Vincenzo, Maria Ferraro, Andreina Bruno performed the experiments and participated to data interpretation. Mark Gjomarkaj contributed to the interpretation of the data. Elisabetta Pace performed the statistical analysis of the data, contributed to data interpretation and manuscript writing and declares that she has had access to and takes responsibility for the integrity of the data.
This work was supported by the Italian National Research Council and Fondazione Ri.MED without a specific grant number.
Compliance with ethical standards
Conflict of interest
All author declare that they have no conflicts of interest.
Research involving human participants and/or animals
This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent is not required for this study.
- 2.Le Chevalier T, Scagliotti G, Natale R et al (2005) Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer 47(1):69–80. https://doi.org/10.1016/j.lungcan.2004.10.014 CrossRefPubMedGoogle Scholar
- 5.Vendrely V, Peuchant E, Buscail E et al (2017) Resveratrol and capsaicin used together as food complements reduce tumor growth and rescue full efficiency of low dose gemcitabine in a pancreatic cancer model. Cancer Lett 390:91–102. https://doi.org/10.1016/j.canlet.2017.01.002 CrossRefPubMedGoogle Scholar
- 7.Kim N, Jeong S, Jing K et al (2015) Docosahexaenoic acid induces cell death in human non-small cell lung cancer cells by repressing mTOR via AMPK activation and PI3K/Akt inhibition. Biomed Res Int. 239764. https://doi.org/10.1155/2015/239764
- 8.Yin Y, Sui C, Meng F, Ma P, Jiang Y (2017) The omega-3 polyunsaturated fatty acid docosahexaenoic acid inhibits proliferation and progression of non-small cell lung cancer cells through the reactive oxygen species-mediated inactivation of the PI3K/Akt pathway. Lipids Health Dis 16(1):87. https://doi.org/10.1186/s12944-017-0474-x CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Chagas TR, Borges DS, de Oliveira PF et al (2017) Oral fish oil positively influences nutritional-inflammatory risk in patients with haematological malignancies during chemotherapy with an impact on long-term survival: a randomised clinical trial. J Hum Nutr Diet, https://doi.org/10.1111/jhn.12471 PubMedGoogle Scholar
- 16.Sanchez-Lara K, Turcott JG, Juarez-Hernandez E et al (2014) Effects of an oral nutritional supplement containing eicosapentaenoic acid on nutritional and clinical outcomes in patients with advanced non-small cell lung cancer: randomised trial. Clin Nutr 33(6):1017–1023. https://doi.org/10.1016/j.clnu.2014.03.006 CrossRefPubMedGoogle Scholar
- 18.Manni A, El-Bayoumy K, Skibinski CG et al (2015) Combination of antiestrogens and omega-3 fatty acids for breast cancer prevention. Biomed Res Int 638645. https://doi.org/10.1155/2015/638645
- 22.Cipollina C, Salvatore SR, Muldoon MF, Freeman BA, Schopfer FJ (2014) Generation and dietary modulation of anti-inflammatory electrophilic omega-3 fatty acid derivatives. Plos One 9(4)ARTN e94836. https://doi.org/10.1371/journal.pone.0094836
- 33.van Moorsel CJ, Veerman G, Bergman AM et al (1997) Combination chemotherapy studies with gemcitabine. Semin Oncol 24(2 Suppl 7): S7-17–S7-23Google Scholar
- 35.Peters GJ, Bergman AM, Ruiz van VW, Haperen et al (1995) Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 4(Suppl 11):72–79Google Scholar