Mechanism for the antitumor and anticachectic effects of n-3 fatty acids

Dietary intake of the n-6 fatty acid (FA) linoleic acid (LA) has a strong g rowth-promoting effect on many rodent tumors and human tumor xenografts gro wn in immunodeficient rodents. n-3 FAs such as alpha-linolenic and eicosape ntaenoic acids (EPAs), which differ from LA and arachidonic acid, respectiv ely, by only a single double bond in the n-3 position, are recognized cance r chemopreventive and anticachectic agents. Understanding how this seemingl y small structural difference leads to such remarkable functional differenc es has been a challenge. In a previous study, we showed that LA uptake, [H- 3]thymidine incorporation into DNA, and total DNA content were decreased in tissue-isolated hepatoma 7288CTC perfused ill situ with arterial blood con taining alpha-linolenic acid, EPA, or docosahexaenoic acids. The K-i for th e inhibition of LA uptake and [H-3]thymidine incorporation by alpha-linolen ic acid was 0.18 and 0.25 mM, respectively, Here we show that the addition of alpha-linolenic acid or EPA to arterial blood inhibits tumor FA uptake, including LA, and the subsequent conversion of LA to the mitogen 13-hydroxy octadecadienoic acid (13-HODE) in vivo and during perfusion in situ, [H-3]T hymidine incorporation during perfusion in situ was also inhibited. Additio n of 13-MODE to the arterial blood reversed the inhibition of [H-3]thymidin e incorporation but had no effect on FA uptake, These two n-3 FAs also inhi bited FA transport in inguinal fat pads in vivo and during perfusion in sit u in fed QA uptake) and fasted (FA release) rats. The effects of EPA and al pha-linolenic acid on transport of saturated, monounsaturated, and n-6 poly unsaturated FAs in hepatoma 7288CTC and inguinal fat pads during perfusion in situ were reversed by the addition of forskolin (1 mu M), pertussis toxi n (0.5 mu g/ml), or 8-bromo-cyclic AMP (10 mu M) to the arterial blood. We conclude that the antitumor and anticachectic effects of n-3 FAs on hepatom a 7288CTC and inguinal fat pads in vivo result from an inhibition of FA tra nsport. These inhibitions are mediated by a putative n-3 FA receptor via a G(i) protein-coupled signal transduction pathway that decreases intracellul ar cyclic AMP. A specific decrease in LA uptake and its conversion to the m itogen 13-HODE causes the tumor growth inhibition.