Cytochrome P450 epoxygenases and cancer: A genetic and a molecular perspective.

Cytochrome CYP450 epoxygenases catalyze the epoxidation of polyunsaturated fatty acids including arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid. The arachidonic acid-derived products are potent pro-angiogenic lipids and promote tumor development and growth. On the other hand, eicosapentaenoic acid- and docosahexaenoic acid-derived products inhibit angiogenesis and play a protective role in certain pathological conditions including cancer. Increased expression of CYP2C epoxygenases, together with increased levels of their arachidonic acid-derived products, is often observed in tumors and tumor-associated vasculature, making these enzymes an ideal target for anti-cancer therapies. Yet, given the pro- and anti-angiogenic action of these enzymes, a better understanding of the specific roles of their products in the regulation of endothelial cell function and cancer development is required. In this review, we provide an overview of the role of CYP450 epoxygenase-derived lipids, with emphasis on arachidonic acid-derived products, in the regulation of endothelial cell function both in physiological and pathological conditions. Moreover, we discuss the impact of genetic polymorphisms in CYP450 epoxygenases on cancer risk, and we discuss advantages and limitation of approaches to target these enzymes and their products in pathological angiogenesis and cancer.