title: Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis.
abstract: Prostaglandins derived from the cyclooxygenase (COX) pathway and epoxyeicosatrienoic acids (EETs) from the cytochrome P450/soluble epoxide hydrolase (sEH) pathway are important eicosanoids that regulate angiogenesis and tumorigenesis. COX-2 inhibitors, which block the formation of prostaglandins, suppress tumor growth, whereas sEH inhibitors, which increase endogenous EETs, stimulate primary tumor growth and metastasis. However, the functional interactions of these two pathways in cancer are unknown. Using pharmacological inhibitors as probes, we show here that dual inhibition of COX-2 and sEH synergistically inhibits primary tumor growth and metastasis by suppressing tumor angiogenesis. COX-2/sEH dual pharmacological inhibitors also potently suppress primary tumor growth and metastasis by inhibiting tumor angiogenesis via selective inhibition of endothelial cell proliferation. These results demonstrate a critical interaction of these two lipid metabolism pathways on tumorigenesis and suggest dual inhibition of COX-2 and sEH as a potential therapeutic strategy for cancer therapy.
authors.affiliation: Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616;Department of Food Science, University of Massachusetts-Amherst, Amherst, MA 01003;
authors.forename: Guodong
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Center for Vascular Biology Research andDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors.forename: Dipak
authors.initials: D
authors.lastname: Panigrahy
authors.affiliation: Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616;
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616;
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Biomedical Engineering, and.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mahakian
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA 95616;
authors.forename: Hiromi I
authors.initials: HI
authors.lastname: Wettersten
authors.affiliation: Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616;
authors.forename: Jun-Yan
authors.initials: JY
authors.lastname: Liu
authors.affiliation: Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616;
authors.forename: Yanru
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, and.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Ingham
authors.affiliation: Department of Biomedical Engineering, and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Tam
authors.affiliation: Division of Pediatric Oncology, Dana-Farber Cancer Institute, andDepartment of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115; and.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA 95616;US Department of Veterans Affairs Medical Center, Sacramento, CA 95655.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Weiss
authors.affiliation: Department of Biomedical Engineering, and.
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
authors.affiliation: Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616; bdhammock@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D009363:Neoplasm Proteins; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D004851:Epoxide Hydrolases