Effects of fatty acids on liver metastasis of ACL‐15 rat colon cancer cells

Abstract

The effects of eicosapentaenoic acid [EPA; n‐3 polyunsaturated fatty acid (PUFA)], linoleic acid (LA; n‐6 PUFA), and palmitic acid (PA; saturated fatty acid) on 1,2‐dimethylhydrazine‐induced F344 rat colon carcinoma cells (ACL‐15) were investigated in vivo and in vitro. The number and size of liver metastatic foci via a superior mesenteric vein injection of ACL‐15 cells in F344 rats were significantly inhibited in the EPA‐treated group compared with the LA‐treated group (p < 0.01); the PA‐treated animals and those fed commercial rodent chow (standard diet) demonstrated intermediate values. In a dot immunoblotting assay, vascular cell adhesion molecule 1 expression on ACL‐15 cells was downregulated by EPA‐ethyl ester treatment and upregulated by LA‐ethyl ester treatment compared with the untreated control cells, whereas the expression of matrix metalloproteinase 1 and 2 was not influenced by the fatty acid ethyl esters. In a 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, EPA‐ethyl ester suppressed ACL‐15 cell growth in a schedule‐dependent manner, and LA‐ethyl ester showed schedule‐dependent stimulation. In contrast, PA demonstrated no regulatory effect on cell growth at lower concentrations (≤ 5 mg/ml) but concentration‐dependent inhibition at higher concentrations. According to our in vivo cell kinetic study, the difference in tumor growth at the metastatic site was due to different tumor cell proliferation rates; the cell loss rate was not altered. Therefore, the inhibitory effect of liver metastasis on ACL‐15 cells by EPA can be explained by a decreased ability of tumor cell adhesion to the capillary bed (low expression of vascular cell adhesion molecule 1) and a lower potential of tumor cell proliferation (low mitotic rate) at the secondary site.