Targeting 5-Lipoxygenase for Prevention and Treatment of Cancer

Abstract

Aberrant arachidonic acid metabolism has been recognized as a dominant mechanism underlying the development and progression of a range of human cancers. Metabolism of arachidonic acid through the 5-lipoxygenase (5-Lox) pathway generates an array of highly reactive eicosanoids categorized into two distinct groups; the leukotrienes (LTs) and the 5-hydroxyeicosatetraenoids (5-HETEs). Evidence documenting prominent roles of these two groups of eicosanoids in the development and progression of cancer are accumulating rapidly both by in vitro cell culture experiments using cancer cells originating from many tissues, and by in vivo tumor model studies. Moreover, significantly higher levels of expression of 5-Lox has been observed in patient tumor specimens in grade-specific manner, and production of elevated levels of 5-Lox metabolites were observed in cancer cells compared to normal counterparts. Thus, 5-Lox has emerged as a new potential target for the prevention and treatment of cancer. Metabolites of 5-Lox are potent signaling molecules and elicit diverse biological activities that are involved in neoplastic transformation and progression, such as cell proliferation, invasion and motility, and apoptosis-resistance. Blocking 5-Lox activity by pharmacological agents will deprive cancer cells of the critical metabolites for their survival and growth, and thus may be effective in the prevention as well as treatment of cancer. Indeed some studies have already shown promise for using 5-Lox inhibitors for the prevention and treatment of cancers of the prostate, lung, pancreas, brain, esophagus, oral cavity, etc.