ω-3 Polyunsaturated fatty acids and their metabolites as inhibitors of mammalian tumorigenesis

Components of tumorigenesis include uncontrolled proliferation and defects in cell death pathways, as well as increased angiogenesis, in which tumors develop their own blood supply, and metastasis, which enables tumor dissemination. Most anticancer drugs are designed to kill cancer cells but are relatively ineffective against some phases of tumorigenesis. Alternate strategies to prevent tumorigenesis are urgently required and considerable evidence has emerged that omega-3 polyunsaturated fatty acids (PUFAs) derived from certain plants and oily fish are important modulators of tumor cell proliferation, apoptosis, angiogenesis and metastasis. Epidemiological studies in man, as well as experimental studies in animal models and cells, have reported that while omega-6 PUFA accelerate tumorigenesis, omega-3 PUFA have anticancer properties. The over-expression of certain PUFA-metabolizing enzymes in tumors, including cyclooxygenases, lipoxygenases and cytochromes P450 (CYP), has provided the impetus for studies on the roles of biotransformation products in the cancer-modulatory actions of PUFAs. Some omega-6 PUFA metabolites, including PGE(2), 5-HETE and the CYP-derived EETs, stimulate tumorigenesis by activating prostanoid receptors, nuclear receptors and intracellular signal transduction cascades. In contrast, omega-3 PUFA both inhibit the formation of pro-tumorigenic omega-6 PUFA metabolites and generate omega-3 metabolites that are anti-tumorigenic in their own right, including PGE(3) and the 17,18-epoxide of epoxyeicosapentaenoic acid (HETE). Some of these naturally occurring metabolites of omega-3 PUFA formed in human cells may be useful lead compounds for the development of novel agents that inhibit cancer.