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

Publisher:
ACS Publications
Publication Type:
Journal Article
Citation:
Journal of Medicinal Chemistry, 2012, 55 (16), pp. 7163 - 7172
Issue Date:
2012-01
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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 C16C22 were synthesized and evaluated in MDA-MB-468 breast cancer cells that stably overexpressed COX-2 (MDA-COX-2 cells). Longer chain (C19C22) n-3 MUFAs inhibited proliferation, activated apoptosis, decreased PGE2 formation, and decreased cell invasion; C16C18 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 C19C22 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.
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