title: Biologic evaluation of curcumin and structural derivatives in cancer chemoprevention model systems.
abstract: Curcumin is a natural product widely used as a spice in food. It has been shown to inhibit cyclooxygenase (COX)-1 and -2 and to suppress lipopolysaccharide-induced COX-2 and iNOS gene expression. In the present study, curcumin and 22 of its derivatives were evaluated for their chemopreventive potential. Based on COX-2 inhibition, curcumin (IC50=15.9 microM), 1,7-bis(3-fluoro-4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (19) (IC50=23.7 microM) and 2,6-bis(3-fluoro-4-hydroxybenzylidene)cyclohexanone (23) (IC50=5.5 microM) were found to be most potent. Tricyclic derivatives 2,6-bis(4-hydroxy-3-methoxybenzylidene)cyclohexanone (10), 2,6-bis(4-hydroxy-3,5-dimethoxybenzylidene)cyclohexanone (13) and 2,5-bis(4-hydroxy-3,5-dimethoxybenzylidene)cyclopentanone (21) inhibited LPS-induced COX-2 and iNOS gene expression in murine macrophages with potency equal to curcumin. RT-PCR experiments demonstrated suppression of COX-2 and iNOS gene expression occurred at the transcriptional level. The most active compounds in the macrophage assays, 13 and 23, were also the most cytotoxic, however. Topical application of curcumin, 10, 13, 21, and 6, a methoxy derivative of curcumin, showed strong inhibition of 12-O-tetradecanoyl-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity in mouse skin. These data suggest that structural elements responsible for COX-1 and COX-2 inhibition do not correlate well with those responsible for inhibiting COX-2 and iNOS gene expression, but elements capable of inhibiting COX-2 and iNOS gene expression also contribute to inhibition of TPA-induced ODC activity. The most potent compounds in these assays, 10, 13 and 21, as well as curcumin, were further evaluated for inhibition of 7,12-dimethylbenz(a)anthracene (DMBA)-induced preneoplastic lesion formation in a mouse mammary organ culture model, and dose-dependent responses were observed. Most potent effects were at concentrations between 1 and 5 microM for 10, 13 and 21, and at 10 microM for curcumin. These data demonstrate the substitution pattern on the aromatic moiety is especially crucial for activity.
authors.affiliation: Program for Collaborative Research in the Pharmaceutical Sciences and Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gafner
authors.forename: Sang-Kook
authors.initials: SK
authors.lastname: Lee
authors.forename: Muriel
authors.initials: M
authors.lastname: Cuendet
authors.forename: Sophie
authors.initials: S
authors.lastname: Barthélémy
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.forename: Serge
authors.initials: S
authors.lastname: Labidalle
authors.forename: Rajendra G
authors.initials: RG
authors.lastname: Mehta
authors.forename: Charles W
authors.initials: CW
authors.lastname: Boone
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002460:Cell Line; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005260:Female; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D065108:Ornithine Decarboxylase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases
chemical_list: D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D007527:Isoenzymes; D008565:Membrane Proteins; D065108:Ornithine Decarboxylase Inhibitors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; C085852:glucose-3-phosphatase; D010744:Phosphoric Monoester Hydrolases; D003474:Curcumin