Antiproliferative and Antimigratory Actions of Synthetic Long Chain n‑3 Monounsaturated Fatty Acids in Breast Cancer Cells That Overexpress Cyclooxygenase‑2

Cyclooxygenase-2 (COX-2) is overexpressed in many human cancers and converts the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid to prostaglandin E₂ (PGE₂), which drives tumorigenesis; in contrast, n-3 PUFA inhibit tumorigenesis. We tested the hypothesis that these antitumor actions of n-3 PUFA may involve the n-3 olefinic bond. n-3 Monounsaturated fatty acids (MUFAs) of chain length C16–C22 were synthesized and evaluated in MDA-MB-468 breast cancer cells that stably overexpressed COX-2 (MDA-COX-2 cells). Longer chain (C19–C22) n-3 MUFAs inhibited proliferation, activated apoptosis, decreased PGE₂ formation, and decreased cell invasion; C16–C18 analogues were less active. Molecular modeling showed that interactions of Arg120, Tyr355, and several hydrophobic amino acid residues in the COX-2 active site with C19–C22 MUFA analogues were favored. Thus, longer-chain n-3 MUFAs may be prototypes of novel anticancer agents that decrease the formation of PGE₂ in tumor cells that contain high levels of COX-2