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Cancer Chemotherapy and Pharmacology

, Volume 81, Issue 4, pp 705–716 | Cite as

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

  • Liboria Siena
  • Chiara Cipollina
  • Serena Di Vincenzo
  • Maria Ferraro
  • Andreina Bruno
  • Mark Gjomarkaj
  • Elisabetta Pace
Original Article
  • 155 Downloads

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.

Keywords

Lung cancer Apoptosis Anti-cancer drugs Gemcitabine Combination therapy Electrophilic lipids Omega-3 polyunsaturated fatty acids 15-hydroxyprostaglandin dehydrogenase Fas Fas Ligand Caspases 

Abbreviations

DHA

Docosahexaenoic acid

NSCLC

Non-small cell lung cancer

FasL

Fas ligand

n-3 PUFAs

Omega-3 polyunsaturated fatty acids

15-PGDH

15-hydroxyprostaglandin dehydrogenase

GCB

Gemcitabine

Notes

Acknowledgements

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.

Funding

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.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Istituto di Biomedicina e Immunologia Molecolare-Consiglio Nazionale delle RicerchePalermoItaly
  2. 2.Fondazione Ri.MEDPalermoItaly

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