gamma-Linolenic acid (GLA), an essential omega-6
polyunsaturated fatty acid (FA) is an attractive concept as
anticancer agent because it exerts selective cytotoxic on human
breast cancer cells without affecting normal cells. This selective toxicity has been identified to be due, at least in part, to the production of
lipid peroxides and
free radicals. Interestingly, a novel hypothesis for GLA-induced
tumor cell toxicity has recently been proposed. GLA, through a molecular mechanism involving the lipogenic
enzyme fatty acid synthase (FAS), coordinately interrupts the pathways that replenish the pools of metabolic intermediates in the citric acid cycle (cellular anaplerosis). First, supraphysiological concentrations of GLA inhibit glycolysis, while a
cytochrome P450-dependent epoxidation of GLA generates
epoxides metabolites for GLA that would mimic the inhibitory action of standard FAS inhibitors such as
cerulenin and C75. Second, GLA-
epoxide inhibits FAS activity, thus resulting in the accumulation of cytosolic
malonyl-CoA which, in turn, inhibits
carnitine palmitoyl
transferase I (
CPT-I) and prevents FA oxidation. The recent characterization of GLA as a novel regulator of FAS expression in
breast cancer cells supports and further expands this hypothesis, and directly involves FAS-dependent de novo
fatty acid synthesis as the mechanism of GLA-induced toxicity to
tumor cells. We hypothesize that, at low (physiological) concentrations, the inhibitory effect of GLA on FAS-regulated
breast cancer cell survival is not specific and is due to cell toxicity caused by lipid peroxidation. Taking into account that the inhibitory effect of FAs on the expression of FAS in cultured hepatocytes has been shown to be related to a non-specific peroxidative mechanism, a similar GLA-dependent FAS regulatory mechanism involving peroxidative products may occur in normal and neoplastic tissues. At high (supraphysiological) concentrations of GLA, the specific downregulation of FAS gene expression leads to accumulation of the substrate for FAS,
malonyl-CoA, that, as a result of FAS blockade, continue to be generated by the rate-limiting
enzyme of the
fatty acid biosynthetic pathway
acetyl-CoA carboxilase, which is not inhibited in the absence of FAS-catalyzed long chain endogenous
fatty acids. Physiologically, the elevated levels of
malonyl-CoA occurring during FA biosynthesis reduce FA oxidation to prevent a futile cycle of simultaneous FA synthesis and degradation. Paradoxically, high-dose GLA treatments of FAS-overexpressing
breast cancer cells will promote
malonyl-CoA-induced inhibition of
CPT-I and FA oxidation, thus precipitating an energy crisis that triggers decreased proliferation or apoptotic cell death. In summary, this working model presents the concept that the
breast cancer adaptation in FAS expression can be exploited to develop GLA-based dietary interventions aimed at altering the FA synthesis pathway, which appears to be linked to neoplastic transformation and is associated with
tumor virulence and adverse clinical outcome in a subset of human
breast carcinomas.