Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid present in fish oil, may exert cytotoxic and/or cytostatic effects on colon cancer cells when applied individually or in combination with some anticancer drugs. Here we demonstrate a selective ability of subtoxic doses of DHA to enhance antiproliferative and apoptotic effects of clinically useful cytokine TRAIL (tumor necrosis factor-related apoptosis inducing ligand) in cancer but not normal human colon cells. DHA-mediated stimulation of TRAIL-induced apoptosis was associated with extensive engagement of mitochondrial pathway (Bax/Bak activation, drop of mitochondrial membrane potential, cytochrome c release), activation of endoplasmic reticulum stress response (CHOP upregulation, changes in PERK level), decrease of cellular inhibitor of apoptosis protein (XIAP, cIAP1) levels and significant changes in sphingolipid metabolism (intracellular levels of ceramides, hexosyl ceramides, sphingomyelines, sphingosines; HPLC/MS/MS). Interestingly, we found significant differences in representation of various classes of ceramides (especially C16:0, C24:1) between the cancer and normal colon cells treated with DHA and TRAIL, and suggested their potential role in the regulation of the cell response to the drug combination. These study outcomes highlight the potential of DHA for a new combination therapy with TRAIL for selective elimination of colon cancer cells via simultaneous targeting of multiple steps in apoptotic pathways.

• MeSH
• Adenocarcinoma genetics   metabolism   pathology   MeSH
• Apoptosis drug effects   genetics   MeSH
• Cytochromes c secretion   MeSH
• Inhibitor of Apoptosis Proteins MeSH
• eIF-2 Kinase genetics   metabolism   MeSH
• Docosahexaenoic Acids pharmacology   MeSH
• Humans MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Cell Line, Tumor MeSH
• Colonic Neoplasms genetics   metabolism   pathology   MeSH
• bcl-2 Homologous Antagonist-Killer Protein genetics   metabolism   MeSH
• TNF-Related Apoptosis-Inducing Ligand pharmacology   MeSH
• bcl-2-Associated X Protein genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Sphingolipids chemistry   classification   metabolism   MeSH
• Signal Transduction MeSH
• Endoplasmic Reticulum Stress drug effects   MeSH
• Drug Synergism MeSH
• Transcription Factor CHOP genetics   metabolism   MeSH
• X-Linked Inhibitor of Apoptosis Protein genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH