Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis

Guodong Zhang, Dipak Panigrahy, Sung Hee Hwang, Jun Yang, Lisa M. Mahakian, Hiromi I. Wettersten, Jun Yan Liu, Yanru Wang, Elizabeth S. Ingham, Sarah Tam, Mark W. Kieran, Robert H Weiss, Katherine W. Ferrara, Bruce D. Hammock

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48 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)11127-11132
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number30
DOIs
StatePublished - 2014

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    Zhang, G., Panigrahy, D., Hwang, S. H., Yang, J., Mahakian, L. M., Wettersten, H. I., Liu, J. Y., Wang, Y., Ingham, E. S., Tam, S., Kieran, M. W., Weiss, R. H., Ferrara, K. W., & Hammock, B. D. (2014). Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America, 111(30), 11127-11132. https://doi.org/10.1073/pnas.1410432111