Abstract
Some polyunsaturated fatty acids (PUFAs), if not all, have been shown to have tumoricidal action, but their exact mechanism(s) of action is not clear. In the present study, we observed that n-6 PUFA linoleic acid (LA) inhibited tumor cell growth at high concentrations (above 300 μM); while low concentrations (100-200 μM) promoted proliferation. Analysis of cell mitochondrial membrane potential, reactive oxygen species (ROS) formation, malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) activity suggested that anti-cancer action of LA is due to enhanced ROS generation and decreased cell anti-oxidant capacity that resulted in mitochondrial damage. Of the three cell lines tested, semi-differentiated colorectal cancer cells RKO were most sensitive to the cytotoxic action of LA, followed by undifferentiated colorectal cancer cell line (LOVO) while the normal human umbilical vein endothelial cells (HUVEC) were the most resistant (the degree of sensitivity to LA is as follows: RKO > LOVO > HUVEC). LA induced cell death was primed by mitochondrial apoptotic pathway. Pre-incubation of cancer cells with 100 μM LA for 24 hr enhanced sensitivity of differentiated and semi-differentiated cells to the subsequent exposure to LA. The relative resistance of LOVO cells to the cytotoxic action of LA is due to a reduction in the activation of caspase-3. Thus, LA induced cancer cell apoptosis by enhancing cellular oxidant status and inducing mitochondrial dysfunction.
Highlights
Essential fatty acids (EFAs): linoleic acid (LA, n-6, 18:2) and a-linolenic acid (ALA, n-3, 18:3) form precursors to their long chain metabolites g-linolenic acid (GLA, n-6, 18:3), dihomo-GLA (DGLA, n-6, 20:3) and arachidonic acid (AA, n-6, 20:4); and eicosapentaenoic acid (EPA, n-3, 20:5) and docosahexaenoic acid (DHA, n-3, 22:6) respectively [1,2,3]
We evaluated the effect of the fatty acid on three cell lines, two of which were colorectal cancer cell lines, LOVO and RKO, and the human umbilical vein endothelial cells (HUVEC) taken as normal cell control in order to clarify the role of LA in the promotion and inhibition of the growth of cancer cells in vitro
LA suppressed the proliferation of LOVO and RKO cells to a significant degree when supplemented with 300 μM of LA, whereas HUVEC cells showed decreased proliferation only when incubated with 600 μM of LA
Summary
Essential fatty acids (EFAs): linoleic acid (LA, n-6, 18:2) and a-linolenic acid (ALA, n-3, 18:3) form precursors to their long chain metabolites g-linolenic acid (GLA, n-6, 18:3), dihomo-GLA (DGLA, n-6, 20:3) and arachidonic acid (AA, n-6, 20:4); and eicosapentaenoic acid (EPA, n-3, 20:5) and docosahexaenoic acid (DHA, n-3, 22:6) respectively [1,2,3]. It was reported that essential fatty acids and their metabolites suppress tumor cells growth both in vitro and in vivo. It was opined that n-6 fatty acids enhance tumor cell growth whereas n-3 fatty acids are beneficial since they arrest cancer growth This differential action of n-3 and n-6 PUFAs in cancer has been attributed to the formation of pro-inflammatory eicosanoids from n-6 PUFAs whereas products formed from n-3 PUFAs are much less pro-inflammatory in nature [1,2,3,4,5,6,7,10,11,12,13], though Trombetta A, etc. This differential action of n-3 and n-6 PUFAs in cancer has been attributed to the formation of pro-inflammatory eicosanoids from n-6 PUFAs whereas products formed from n-3 PUFAs are much less pro-inflammatory in nature [1,2,3,4,5,6,7,10,11,12,13], though Trombetta A, etc. reported that AA, an n-6 PUFA, decreased human lung-tumor cell growth in a concentration-dependent manner, induction of cell death mainly evident at 100 mM concentration [14]
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