Cytochrome P450 epoxygenase enzymes oxidize arachidonic acid to produce regioisomers of cis-epoxyeicosatrienoic acids (EETs) that have a myriad of functions. The EETs are potent vasodilatory agents, potent anti-inflammatory agents, and inducers of angiogenesis. Because angiogenesis is implicated in the pathological growth of carcinoma cells and the CYP2J2 epoxygenase is found to be up-regulated in many tumors, it has been suggested that inhibitors of CYP2J2 might be anticancer agents. In this issue, Chen et al., describe the synthesis and evaluation of a number of agents structurally related to terfenadine, a known CYP2J2 inhibitor. Several of the molecules attenuated EET production by approximately 60% without affecting CYP2J2 mRNA or protein levels. One of the compounds inhibited proliferation of several tumor cell lines while also blocking adherence and migratory capacity, presumably through measured inhibition of phosphoinositide 3-kinase/Akt signaling. The agents also sensitized the tumor cells toward apoptosis through increased caspase and decreased anti-apoptotic bcl2 family members. In murine xenografts of a breast cancer cell line, one agent significantly blocked tumor growth while also down-regulating metastasis and increasing expression of anticancer genes. No toxicity was observed. Thus, specific inhibitors of CYP2J2 show promise as a new class of anticancer therapeutics.
See article at J Pharmacol Exp Ther 2009, 329:908-918.
- The American Society for Pharmacology and Experimental Therapeutics