Antiproliferative and antimigratory actions of synthetic long chain n-3 monounsaturated fatty acids in breast cancer cells that overexpress cyclooxygenase-2
Date
2012
Authors
Cui, P.
Rawling, T.
Bourget, K.
Kim, T.
Duke, C.C.
Doddareddy, M.R.
Hibbs, D.E.
Zhou, F.
Tattam, B.
Petrovic, N.
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Journal article
Citation
Journal of Medicinal Chemistry, 2012; 55(16):7163-7172
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Abstract
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.
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Data source: Supporting information, https://doi.org/10.1021/jm300673z
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Copyright 2012 American Chemical Society