CYP epoxygenase derived EETs: from cardiovascular protection to human cancer therapy

Arachidonic acids are converted to eicosanoid mediators by the distinct enzyme systems: cyclooxygenase, lipoxygenase and cytochrome P450 (CYP) monooxygenase pathways (ω/ω⁻¹-hydroxylases and epoxygenases). CYP2J2, CYP2C8 and CYP2C9 are the predominant epoxygenase isoforms abundantly expressed in the endothelium, myocardium, and kidney in human. The primary epoxidation products by epoxygenases are four regioisomers of cis-epoxyeicosatrienoic acids (EETs): 5,6-, 8,9-, 11,12-, and 14,15-EETs. Numerous studies demonstrated that the cardiovascular protective effects of CYP epoxygenases and EETs range from vasodilation, anti-hypertension, pro-angiogenesis, anti-atherosclerosis, and anti-inflammation to anti-injury caused by ischemia-reperfusion. The roles of arachidonic acids and its metabolites in cancer biology have recently attracted great attentions. However, CYP epoxygenase derived EETs and cancer has received little attention. It was demonstrated that CYP epoxygenases and EETs are significantly upregulated in human tumors and promote tumor progression and metastasis. Additionally, specific inhibitors of CYP2J2, derived from terfenadine, exhibit strong anti-tumor activity in vitro and in vivo. It is implicated that CYP2J2 may be a therapeutic target for treating human cancers.