In vivo studies have demonstrated that high fat fish oil (HFFO) diets with high levels of
n-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA; 20:5n-3) can inhibit the formation of chemically-induced colon tumors during both the initiation and post-initiation phases of colorectal carcinogenesis compared with high fat corn oil (HFCO) diets which are rich in n-6 PUFAs such as linoleic acid (LA: 18:2n-6).
Studies described in this thesis show that HFFO diets also protect against the initiation of aberrant crypt foci (ACF; precursor lesions of colon cancer) in F344 rats compared to HFCO diets. Furthermore, EPA also inhibited the proliferation of human colon adenocarcinoma Caco-2 cells compared to LA. The mechanism responsible for the inhibitory effects of n-3 PUFAs such as EPA on colorectal tumors may partly be related to inhibition of PGE 2 synthesis from arachidonic acid (AA; 20:4n-6). Plasma levels of PGE 2 were indeed lower in HFFO fed rats compared to HFCO fed rats. However, reductions in PGE 2 synthesis by EPA compared to AA in Caco-2 cells did not lead to differential effects on cell proliferation, which suggests that PGE 2 is not directly involved in regulation of cell proliferation in colon cancer cells by n-6 and n-3 PUFAs.
Our results suggest that lipid peroxidation-induced oxidative stress might be an important mechanism by which n-3 PUFAs possess anti-carcinogenic effects. This is supported by the fact that HFFO diets with a high amount of EPA increased the amount of lipid peroxidation in F344 rats compared to HFCO diets with a high amount of LA. Levels of malondialdehyde, which is an endproduct of lipid peroxidation were also increased after incubation of Caco-2 cells with EPA. Furthermore, transcription of genes involved in oxidative stress is increased in HFFO fed rats, whereas addition of antioxidants diminishes the anticancer effects of n-3 PUFAs in Caco-2 cells, which also suggests that oxidation of n-3 PUFAs underlies their anticancer effects. Overall, the results might imply that n-3 PUFAs protect against colon carcinogenesis via increased oxidative stress that can ultimately lead to inhibition of cell proliferation to prevent clonal expansion or induction of apoptosis to stimulate disposal of damaged colonic epithelial cells. Diets enriched with high levels of n-3 PUFAs may thus have beneficial colon cancer inhibiting effects, which may be reduced by high levels of dietary antioxidants.
|Qualification||Doctor of Philosophy|
|Award date||12 Sep 2003|
|Place of Publication||Wageningen|
|Publication status||Published - 2003|
- colorectal cancer
- unsaturated fatty acids