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.

Inflammation and skeletal metastasis

“…Antiinflammatory therapies have been evaluated with success for targeting tumor progression and metastasis, and they are associated with reduced infiltration of bone marrow-derived myeloid cells and the prometastatic macrophages. 17,[186][187][188][189][190] A different approach to target metastasis involves the direct stimulation of antitumor immunity. For example, transformation of macrophages from M2 to M1 type has been demonstrated to recruit cytotoxic T cells and elicit antitumor responses.…”

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids

“…Similarly, when a COX (celecoxib) and sEH inhibitor (trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid; t-AUCB) were administered simultaneously to mice, tumor growth was much more inhibited than administration of the same two inhibitors alone, as shown in Fig. 1B (15). These results indicate that coincubation with a COX and sEH inhibitor produces a synergistic effect, better at inhibiting primary tumor growth and metastasis through the suppression of cancer angiogenesis.…”

“…1A). Inhibition of sEH prolongs EET biological activity, potentiating their angiogenic activity, leading to increased tumor growth and metastasis in some systems (12,15) (Fig. 1B).…”

“…Angiogenesis stimulated from exposure to ARA can be mediated using COX inhibitors, which suppress the formation of prostaglandins (16). Compared with sEH inhibitors, COX inhibitors (i.e., the COX-2 selective inhibitor celecoxib) suppress angiogenesis and tumor growth, whereas sEH inhibitors alone tend to stimulate these same responses in animals on a high-omega-6 fat diet (15). It was therefore surprising that administration of a dual sEH and COX inhibitor led to an antiangiogenic and anticancer response more pronounced than administration of these inhibitors alone (15).…”

“…Compared with sEH inhibitors, COX inhibitors (i.e., the COX-2 selective inhibitor celecoxib) suppress angiogenesis and tumor growth, whereas sEH inhibitors alone tend to stimulate these same responses in animals on a high-omega-6 fat diet (15). It was therefore surprising that administration of a dual sEH and COX inhibitor led to an antiangiogenic and anticancer response more pronounced than administration of these inhibitors alone (15). Similarly, when a COX (celecoxib) and sEH inhibitor (trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid; t-AUCB) were administered simultaneously to mice, tumor growth was much more inhibited than administration of the same two inhibitors alone, as shown in Fig.…”