N-3 Polyunsaturated Fatty Acids as Signal Transduction Modulators and Therapeutical Agents in Cancer

Abstract

Epidemiological and experimental studies have established the beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) on cancer. In particular, wide information is available regarding their effects on hormone responsive tumors, such as prostatic and mammary cancer, and tumors originating from colon. Recent studies have focused upon the improvement of chemotherapy effects when different drug treatments are accompanied by n-3 PUFA administration. The growth inhibitory action elicited by these fatty acids on tumors seems to be related to their ability to induce apoptosis and cell cycle arrest in cancer cells and to inhibit neo-angiogenesis. Different molecular mechanisms have been hypothesized to explain their anticancer effects, and this field is receiving increased attention. For a long time n-3 PUFAs have been considered to function only as prooxidant agents, competitors for arachidonic acid metabolism, or modifiers of membrane microenvironment and fluidity in cells. However, more recently, they have been shown to act as transcription regulators, being able to modulate the activity of different transcription factors, including NFkB, peroxisome proliferator-activated receptors, retinoid X receptors, and HIF-1. The expression of a wide array of genes involved in the regulation of cell proliferation, apoptosis, neo-angiogenesis and invasion of tumors have been shown to be modulated by n-3 PUFAs (proteins of BCL-2 family, cyclins and cyclin dependent kinase inhibitors, protein-kinases and phosphatases, COX-2, 5- LOX, VEGF and matrix-metalloproteinases). The modulating action brought about by n-3 PUFAs on the expression of lipid metabolism enzymes, such as fatty acids synthase and 3-hydroxy-3-methyl-glutaryl-CoA (HMG)-CoA reductase, have been recently involved in the anticarcinogenic action of these fatty acids. Telomerases, DNA topoisomerases and DNA polymerases are further molecular targets critical in the growth and survival of cancer cells recently observed to be modulated by n-3 PUFAs. The aim of this review is to examine the molecular mechanisms invoked so far in order to explain the anticancer effects of n-3 PUFAs. The definitive comprehension of the molecular mechanisms involved appears to be crucial to establish the appropriateness of n-3 PUFAs as chemopreventive or adjuvant therapeutic agents in human cancer. Keywords: n-3 PUFAs, DHA, EPA, chemoprevention, cancer-therapy, signal-transduction