title: Antiproliferative and antimigratory actions of synthetic long chain n-3 monounsaturated fatty acids in breast cancer cells that overexpress cyclooxygenase-2.
abstract: Cyclooxygenase-2 (COX-2) is overexpressed in many human cancers and converts the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid to prostaglandin E(2) (PGE(2)), 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 PGE(2) 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 PGE(2) in tumor cells that contain high levels of COX-2.
authors: Pharmacogenomics and Drug Development Group, Faculty of Pharmacy, University of Sydney, NSW 2006, Australia.
authors: Pei H
authors: PH
authors: Cui
authors: Tristan
authors: T
authors: Rawling
authors: Kirsi
authors: K
authors: Bourget
authors: Terry
authors: T
authors: Kim
authors: Colin C
authors: CC
authors: Duke
authors: Munikumar R
authors: MR
authors: Doddareddy
authors: David E
authors: DE
authors: Hibbs
authors: Fanfan
authors: F
authors: Zhou
authors: Bruce N
authors: BN
authors: Tattam
authors: Nenad
authors: N
authors: Petrovic
authors: Michael
authors: M
authors: Murray
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D015525:Fatty Acids, Omega-3 / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007797:Laminin; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D011509:Proteoglycans; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D015525:Fatty Acids, Omega-3; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D051546:Cyclooxygenase 2; D015232:Dinoprostone