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