Chemoprevention of prostate cancer progression: Targeting 15-lipoxygenase (15-LO)-1 and cyclooxygenase (COX)-2 pathways by dietary omega-3 fatty acids.

B229

The main objective of our study was to determine the bioavailability of dietary omega (n)-3 to the prostate tumor and the feasibility of targeting 15-lipoxygenase (15-LO)-1 and cyclooxygenase (COX)-2 pathways. Tumor growth and apoptosis were examined as primary end-points after administration of a short-term (5-week) n-3 fatty acids diet. Nude mice were injected subcutaneously (s.c.) in the right and left lateral flank with 1 x 106 prostate cancer LAPC-4 tumor cells and randomly divided into three different isocaloric (and same % of total fat) diet groups: n-6 linoleic acid (LA), n-3 stearidonic acid (SDA- a precursor of EPA), and normal fat diets. Levels of n-6 LA, AA and n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in membrane phospholipids of red blood cell cells reflected dietary changes and correlated with the levels observed in tumors. There were no apparent differences observed in either the % unsaturated or % saturated fatty acids in the total phospholipids, suggesting that the tumors maintained membrane fluidity and functionality of proteins in the membrane. In comparison with mice fed the normal diet, we observed a 2.7-fold increase in the n-6/n-3 ratio in tumors from LA-fed mice and a 4.2-fold decrease in the ratio in tumors from the SDA-fed mice. Half of the mice from each PUFA group were switched to the opposing diet while the other half of the mice remained on their original diet. After 5 weeks, tumors were examined for growth, lipids, enzyme activities, apoptosis and proliferation. Tumors from the LA-diet fed mice exhibited the most rapid growth as compared with tumors from the control and SDA diet fed mice. Moreover, a diet switch from LA to SDA caused a dramatic decrease in the growth of tumors in 5 weeks whereas tumors grew more aggressively when mice were switched from a SDA to LA diet. Similarly, we observed increased estimated activity of delta (Δ)-6-desaturase enzyme and decreased Δ-5-desaturase activity in tumors from mice fed the SDA-diet and the decreased activity in tumors from mice fed the LA-diet. Ki-67 and percent (%) proliferation index increased in tumors from the n-6 diet fed mice as compared with tumors from the n-3 SDA-fed mice. Further, increased apoptosis as assessed by caspase-3 was observed in tumors from n-3 SDA-fed mice versus tumors from n-6 diet fed mice. SDA and EPA did not inhibit the 15-LO-1 or COXs enzymes. Thus the observed differences in tumor growth reflect the substrate competition of n-3 with n-6 fatty acids. This study provides evidence that: (a) the rate of prostate tumor growth can be modulated by the manipulation of n-6:n-3 ratios via diet, and (b) EPA promotes apoptosis and decreases proliferation in tumors by competing with n-6 fatty acids for 15-LO-1, and COX-2 activity. Thus, purified EPA from fish oil could potentially serve as a promising dietary intervention agent in slowing prostate cancer progression.