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01-04-2018 | Original Article

Electrophilic derivatives of omega-3 fatty acids counteract lung cancer cell growth

Authors: Liboria Siena, Chiara Cipollina, Serena Di Vincenzo, Maria Ferraro, Andreina Bruno, Mark Gjomarkaj, Elisabetta Pace

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2018

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61(4): 212–236. https://doi.org/10.3322/caac.20121 CrossRef

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 CrossRefPubMed

Schiller JH, Harrington D, Belani CP et al (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med, 346(2): 92–98. https://doi.org/10.1056/NEJMoa011954 CrossRef

Sooman L, Gullbo J, Bergqvist M et al (2017) Synergistic effects of combining proteasome inhibitors with chemotherapeutic drugs in lung cancer cells. BMC Res Notes 10(1):544. https://doi.org/10.1186/s13104-017-2842-z CrossRefPubMedPubMedCentral

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 CrossRefPubMed

Tuya N, Wang Y, Tong L et al (2017) Trichosanthin enhances the antitumor effect of gemcitabine in non-small cell lung cancer via inhibition of the PI3K/AKT pathway. Exp Ther Med 14(6):5767–5772. https://doi.org/10.3892/etm.2017.5286 PubMedPubMedCentral

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

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 CrossRefPubMedPubMedCentral

Zhang G, Panigrahy D, Mahakian LM et al (2013) Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis. Proc Natl Acad Sci USA 110(16):6530–6535. https://doi.org/10.1073/pnas.1304321110 CrossRefPubMedPubMedCentral

10.

Cockbain AJ, Toogood GJ, Hull MA (2012) Omega-3 polyunsaturated fatty acids for the treatment and prevention of colorectal cancer. Gut 61(1): 135–149. https://doi.org/10.1136/gut.2010.233718 CrossRef

11.

Yao QH, Zhang XC, Fu T et al (2014) omega-3 polyunsaturated fatty acids inhibit the proliferation of the lung adenocarcinoma cell line A549 in vitro. Mol Med Rep 9(2):401–406. https://doi.org/10.3892/mmr.2013.1829 CrossRefPubMed

12.

Zajdel A, Wilczok A, Tarkowski M. (2015) Toxic effects of n-3 polyunsaturated fatty acids in human lung A549 cells. Toxicol In Vitro, 30(1 Pt B): 486–491. https://doi.org/10.1016/j.tiv.2015.09.013

13.

Miccadei S, Masella R, Mileo AM S Gessani (2016) Omega3 polyunsaturated fatty acids as immunomodulators in colorectal cancer: new potential role in adjuvant therapies. Front Immunol 7:486. https://doi.org/10.3389/fimmu.2016.00486 CrossRefPubMedPubMedCentral

14.

Abdelmagid SA, MacKinnon JL, Janssen SM, Ma DW (2016) Role of n-3 polyunsaturated fatty acids and exercise in breast cancer prevention: identifying common targets. Nutr Metab Insights 9:71–84. https://doi.org/10.4137/NMI.S39043 CrossRefPubMedPubMedCentral

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 PubMed

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 CrossRefPubMed

17.

Finocchiaro C, Segre O, Fadda M et al (2012) Effect of n-3 fatty acids on patients with advanced lung cancer: a double-blind, placebo-controlled study. Br J Nutr 108(2): 327–333. https://doi.org/10.1017/S0007114511005551 CrossRef

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

19.

Murphy RA, Mourtzakis M, Chu QS et al (2011) Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer. Cancer 117(16):3774–3780. https://doi.org/10.1002/cncr.25933 CrossRefPubMed

20.

Li S, Qin J, Tian C et al (2014) The targeting mechanism of DHA ligand and its conjugate with Gemcitabine for the enhanced tumor therapy. Oncotarget 5(11):3622–3635. https://doi.org/10.18632/oncotarget.1969 CrossRefPubMedPubMedCentral

21.

Haqq J, Howells LM, Garcea G, Dennison AR (2016) Targeting pancreatic cancer using a combination of gemcitabine with the omega-3 polyunsaturated fatty acid emulsion, Lipidem. Mol Nutr Food Res. 60(6): 1437–1447. https://doi.org/10.1002/mnfr.201500755 CrossRefPubMed

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

23.

Wendell SG, Golin-Bisello F, Wenzel S et al (2015) 15-Hydroxyprostaglandin dehydrogenase generation of electrophilic lipid signaling mediators from hydroxy omega-3 fatty acids. J Biol Chem. 290(9): 5868–5880. https://doi.org/10.1074/jbc.M114.635151 CrossRefPubMedPubMedCentral

24.

Keenan AH, Pedersen TL, Fillaus K et al (2012) Basal omega-3 fatty acid status affects fatty acid and oxylipin responses to high-dose n3-HUFA in healthy volunteers. J Lipid Res 53(8):1662–1669. https://doi.org/10.1194/jlr.P025577 CrossRef

25.

Yang P, Cartwright C, Chan D et al (2014) Anticancer activity of fish oils against human lung cancer is associated with changes in formation of PGE2 and PGE3 and alteration of Akt phosphorylation. Mol Carcinog 53(7): 566–577. https://doi.org/10.1002/mc.22008 CrossRef

26.

Woodcock CC, Huang Y, Woodcock SR et al (2017) Nitro-fatty acid inhibition of triple negative breast cancer cell viability, migration, invasion and tumor growth. J Biol Chem, https://doi.org/10.1074/jbc.M117.814368

27.

Groeger AL, Cipollina C, Cole MP et al (2010) Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids. Nat Chem Biol 6(6): 433–441. https://doi.org/10.1038/nchembio.367 CrossRef

28.

Fink SP, Yamauchi M, Nishihara R et al (2014) Aspirin and the risk of colorectal cancer in relation to the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD). Sci Transl Med 6(233):233re2. https://doi.org/10.1126/scitranslmed.3008481 CrossRefPubMedPubMedCentral

29.

Siena L, Pace E, Ferraro M et al (2014) Gemcitabine sensitizes lung cancer cells to Fas/FasL system-mediated killing. Immunology 141(2): 242–255. https://doi.org/10.1111/imm.12190 CrossRef

30.

Shameem IA, Kurisu H, Matsuyama H, Shimabukuro T, Naito K (1994) Direct and indirect effects of recombinant human granulocyte-colony stimulating factor on in vitro colony formation of human bladder cancer cells. Cancer Immunol Immunother 38(6):353–357CrossRefPubMed

31.

Dela Cruz CS, Tanoue LT, Matthay RA (2011) Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 32(4): 605–644. https://doi.org/10.1016/j.ccm.2011.09.001 CrossRef

32.

Hu X, Pu K, Feng X et al (2016) Role of gemcitabine and pemetrexed as maintenance therapy in advanced NSCLC: a systematic review and meta-analysis of randomized controlled trials. PLoS One 11(3):e0149247. https://doi.org/10.1371/journal.pone.0149247 CrossRefPubMedPubMedCentral

33.

van Moorsel CJ, Veerman G, Bergman AM et al (1997) Combination chemotherapy studies with gemcitabine. Semin Oncol 24(2 Suppl 7): S7-17–S7-23

34.

Peters GJ, Ruiz VW, van Haperen AM, Bergman et al (1996) Preclinical combination therapy with gemcitabine and mechanisms of resistance. Semin Oncol 23(5 Suppl 10):16–24PubMed

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):72–79

36.

Bergman AM, Ruiz VW, van Haperen G, Veerman CM (1996) Kuiper, and G.J. Peters. Synergistic interaction between cisplatin and gemcitabine in vitro. Clin Cancer Res 2(3):521–530PubMed

37.

van Moorsel CJ, Pinedo HM, Veerman G et al (1999) Mechanisms of synergism between cisplatin and gemcitabine in ovarian and non-small-cell lung cancer cell lines. Br J Cancer 80(7): 981–990. https://doi.org/10.1038/sj.bjc.6690452 CrossRef

38.

van Moorsel CJ, Pinedo HM, Smid K et al (2000) Schedule-dependent pharmacodynamic effects of gemcitabine and cisplatin in mice bearing Lewis lung murine non-small cell lung tumours. Eur J Cancer 36(18):2420–2429CrossRefPubMed

39.

Ferreira CG, Span SW, Peters GJ, Kruyt FA, Giaccone G (2000) Chemotherapy triggers apoptosis in a caspase-8-dependent and mitochondria-controlled manner in the non-small cell lung cancer cell line NCI-H460. Cancer Res 60(24):7133–7141PubMed

40.

Ferreira CG, Tolis C, Span SW et al (2000) Drug-induced apoptosis in lung cnacer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway. Clin Cancer Res 6(1):203–212PubMed

41.

Morgan MA, Parsels LA, Kollar LE et al (2008) The combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation in pancreatic cancer. Clin Cancer Res 14(16): 5142–5149. https://doi.org/10.1158/1078-0432.CCR-07-4072 CrossRefPubMedPubMedCentral

42.

Yu X, Li Y, Yu Y et al (2016) Associations between FAS rs2234767 and FASL rs763110 polymorphisms and the risk of lung cancer: a meta-analysis of 39,736 subjects. Onco Targets Ther 9:2049–2056. https://doi.org/10.2147/OTT.S102723 CrossRefPubMedPubMedCentral

43.

Fulda S (2013) Regulation of cell death in cancer-possible implications for immunotherapy. Front Oncol 3:29. https://doi.org/10.3389/fonc.2013.00029 PubMedPubMedCentral

44.

Nazim UM, Moon JH, Lee YJ, Seol JW, Park SY (2017) PPARgamma activation by troglitazone enhances human lung cancer cells to TRAIL-induced apoptosis via autophagy flux. Oncotarget 8(16):26819–26831. https://doi.org/10.18632/oncotarget.15819 CrossRefPubMedPubMedCentral

45.

Pace E, Melis M, Siena L et al (2000) Effects of gemcitabine on cell proliferation and apoptosis in non-small-cell lung cancer (NSCLC) cell lines. Cancer Chemother Pharmacol. 46(6): 467–476. https://doi.org/10.1007/s002800000183 CrossRef

46.

Chang CL, Hsu YT, Wu CC et al (2013) Dose-dense chemotherapy improves mechanisms of antitumor immune response. Cancer Res 73(1): 119–127. https://doi.org/10.1158/0008-5472.CAN-12-2225 CrossRef

47.

Pace E, Siena L, Ferraro M et al (2006) Role of prostaglandin E2 in the invasiveness, growth and protection of cancer cells in malignant pleuritis. Eur J Cancer 42(14):2382–2389. https://doi.org/10.1016/j.ejca.2006.03.022 CrossRefPubMed

48.

Huang G, Eisenberg R, Yan M et al (2008) 15-Hydroxyprostaglandin dehydrogenase is a target of hepatocyte nuclear factor 3beta and a tumor suppressor in lung cancer. Cancer Res. 68(13): 5040–5048. https://doi.org/10.1158/0008-5472.CAN-07-6575 CrossRef

49.

Hughes D, Otani T, Yang P et al (2008) NAD+-dependent 15-hydroxyprostaglandin dehydrogenase regulates levels of bioactive lipids in non-small cell lung cancer. Cancer Prev Res (Phila) 1(4): 241–249. https://doi.org/10.1158/1940-6207.CAPR-08-0055.CrossRef

50.

Li Y, Li S, Sun D, Song L, Liu X (2014) Expression of 15-hydroxyprostaglandin dehydrogenase and cyclooxygenase-2 in non-small cell lung cancer: correlations with angiogenesis and prognosis. Oncol Lett 8(4):1589–1594. https://doi.org/10.3892/ol.2014.2371 CrossRefPubMedPubMedCentral

51.

Ding Y, Tong M, Liu S, Moscow JA, Tai HH (2005) NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer. Carcinogenesis 26(1):65–72. https://doi.org/10.1093/carcin/bgh277 CrossRefPubMed

52.

Lu D, Han C, Wu T (2014) 15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPARgamma-mediated activation of p21WAF1/Cip1. Oncogene 33(9):1101. https://doi.org/10.1038/onc.2013.69 -12.CrossRefPubMed

53.

Yao L, Han C, Song K et al (2015) Omega-3 polyunsaturated fatty acids upregulate 15-PGDH expression in cholangiocarcinoma cells by inhibiting miR-26a/b expression. Cancer Res. 75(7): 1388–1398. https://doi.org/10.1158/0008-5472.CAN-14-2561 CrossRefPubMedPubMedCentral

Title: Electrophilic derivatives of omega-3 fatty acids counteract lung cancer cell growth
Authors: Liboria Siena
Chiara Cipollina
Serena Di Vincenzo
Maria Ferraro
Andreina Bruno
Mark Gjomarkaj
Elisabetta Pace
Publication date: 01-04-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-018-3538-3

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