PMID- 25024195 OWN - NLM STAT- MEDLINE DCOM- 20141031 LR - 20220310 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 111 IP - 30 DP - 2014 Jul 29 TI - Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis. PG - 11127-32 LID - 10.1073/pnas.1410432111 [doi] AB - 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. FAU - Zhang, Guodong AU - Zhang G AD - 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; FAU - Panigrahy, Dipak AU - Panigrahy D AD - Center for Vascular Biology Research andDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; FAU - Hwang, Sung Hee AU - Hwang SH AD - Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616; FAU - Yang, Jun AU - Yang J AD - Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616; FAU - Mahakian, Lisa M AU - Mahakian LM AD - Department of Biomedical Engineering, and. FAU - Wettersten, Hiromi I AU - Wettersten HI AD - Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA 95616; FAU - Liu, Jun-Yan AU - Liu JY AD - Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616; FAU - Wang, Yanru AU - Wang Y AD - Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616; FAU - Ingham, Elizabeth S AU - Ingham ES AD - Department of Biomedical Engineering, and. FAU - Tam, Sarah AU - Tam S AD - Department of Biomedical Engineering, and. FAU - Kieran, Mark W AU - Kieran MW AD - Division of Pediatric Oncology, Dana-Farber Cancer Institute, andDepartment of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115; and. FAU - Weiss, Robert H AU - Weiss RH AD - Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA 95616;US Department of Veterans Affairs Medical Center, Sacramento, CA 95655. FAU - Ferrara, Katherine W AU - Ferrara KW AD - Department of Biomedical Engineering, and. FAU - Hammock, Bruce D AU - Hammock BD AD - Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616; bdhammock@ucdavis.edu. LA - eng GR - P30 CA093373/CA/NCI NIH HHS/United States GR - P42ES04699/ES/NIEHS NIH HHS/United States GR - HHSN268201000043C/HL/NHLBI NIH HHS/United States GR - R01 ES002710/ES/NIEHS NIH HHS/United States GR - HHSN268201000043/PHS HHS/United States GR - P42 ES004699/ES/NIEHS NIH HHS/United States GR - R01 CA134659/CA/NCI NIH HHS/United States GR - R01 CA135401/CA/NCI NIH HHS/United States GR - U54 OH07550/OH/NIOSH CDC HHS/United States GR - U54 OH007550/OH/NIOSH CDC HHS/United States GR - R01 CA112356/CA/NCI NIH HHS/United States GR - R01 CA148633/CA/NCI NIH HHS/United States GR - R01 ES02710/ES/NIEHS NIH HHS/United States GR - R01 DK082690/DK/NIDDK NIH HHS/United States GR - R01 CA103828/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20140714 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Antineoplastic Agents) RN - 0 (Cyclooxygenase 2 Inhibitors) RN - 0 (Neoplasm Proteins) RN - EC 1.14.99.- (Ptgs2 protein, mouse) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 3.3.2.- (Epoxide Hydrolases) SB - IM MH - Animals MH - Antineoplastic Agents MH - Cyclooxygenase 2/*metabolism MH - Cyclooxygenase 2 Inhibitors/*pharmacology MH - Drug Synergism MH - *Epoxide Hydrolases/antagonists & inhibitors/metabolism MH - Male MH - Mice MH - Neoplasm Metastasis MH - Neoplasm Proteins/agonists/antagonists & inhibitors/metabolism/*pharmacology MH - *Neoplasms, Experimental/drug therapy/enzymology/pathology PMC - PMC4121808 COIS- Conflict of interest statement: The sponsor (B.D.H.) and a coauthor (S.H.H.) are authors on a patent held by the University of California on the synthesis of the joint cyclooxygenase-soluble epoxide hydrolase inhibitor used as a probe in this study. The patent has not been licensed. EDAT- 2014/07/16 06:00 MHDA- 2014/11/02 06:00 PMCR- 2015/01/29 CRDT- 2014/07/16 06:00 PHST- 2014/07/16 06:00 [entrez] PHST- 2014/07/16 06:00 [pubmed] PHST- 2014/11/02 06:00 [medline] PHST- 2015/01/29 00:00 [pmc-release] AID - 1410432111 [pii] AID - 201410432 [pii] AID - 10.1073/pnas.1410432111 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):11127-32. doi: 10.1073/pnas.1410432111. Epub 2014 Jul 14.