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

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• 作者：Pei H. Cui ; Tristan Rawling ; Kirsi Bourget ; Terry Kim ; Colin C. Duke ; Munikumar R. Doddareddy ; David E. Hibbs ; Fanfan Zhou ; Bruce N. Tattam ; Nenad Petrovic ; Michael Murray
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 23, 2012
• 年：2012
• 卷：55
• 期：16
• 页码：7163-7172
• 全文大小：382K
• 年卷期：v.55,no.16(August 23, 2012)
• ISSN：1520-4804

文摘

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鈥揅22 were synthesized and evaluated in MDA-MB-468 breast cancer cells that stably overexpressed COX-2 (MDA-COX-2 cells). Longer chain (C19鈥揅22) n-3 MUFAs inhibited proliferation, activated apoptosis, decreased PGE₂ formation, and decreased cell invasion; C16鈥揅18 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鈥揅22 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.