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 language | English (US) |
|---|---|
| Pages (from-to) | 11127-11132 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 111 |
| Issue number | 30 |
| DOIs | |
| State | Published - 2014 |
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Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis. / Zhang, Guodong; Panigrahy, Dipak; Hwang, Sung Hee; Yang, Jun; Mahakian, Lisa M.; Wettersten, Hiromi I.; Liu, Jun Yan; Wang, Yanru; Ingham, Elizabeth S.; Tam, Sarah; Kieran, Mark W.; Weiss, Robert H; Ferrara, Katherine W.; Hammock, Bruce D.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 30, 2014, p. 11127-11132.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis
AU - Zhang, Guodong
AU - Panigrahy, Dipak
AU - Hwang, Sung Hee
AU - Yang, Jun
AU - Mahakian, Lisa M.
AU - Wettersten, Hiromi I.
AU - Liu, Jun Yan
AU - Wang, Yanru
AU - Ingham, Elizabeth S.
AU - Tam, Sarah
AU - Kieran, Mark W.
AU - Weiss, Robert H
AU - Ferrara, Katherine W.
AU - Hammock, Bruce D.
PY - 2014
Y1 - 2014
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84904990664&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904990664&partnerID=8YFLogxK
U2 - 10.1073/pnas.1410432111
DO - 10.1073/pnas.1410432111
M3 - Article
C2 - 25024195
AN - SCOPUS:84904990664
VL - 111
SP - 11127
EP - 11132
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 30
ER -