Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells

Palmitoylethanolamide (PEA) has been shown to act in synergy with anandamid e (arachidonoylethanolamide; AEA), an endogenous agonist of cannabinoid rec eptor type I (CB1). This synergistic effect was reduced by the CB2 cannabin oid receptor antagonist SR144528, although PEA does not activate either CB1 or CB2 receptors. Here we show that PEA potently enhances the anti-prolife rative effects of AEA on human breast cancer cells (HBCCs), in part by inhi biting the expression of fatty acid amide hydrolase (FAAH), the major enzym e catalysing AEA degradation. PEA (1-10 muM) enhanced in a dose-related man ner the inhibitory effect of AEA on both basal and nerve growth factor (NGF )-induced HBCC proliferation, without inducing any cytostatic effect by its elf. PEA (5 muM) decreased the IC50 values for AEA inhibitory effects by 3- 6-fold. This effect was not blocked by the CB2. receptor antagonist SR14452 8, and was not mimicked by a selective agonist of CB2 receptors. PEA enhanc ed AEA-evoked inhibition of the expression of NGF Trk receptors, which unde rlies the anti-proliferative effect of the endocannabinoid on NGF-stimulate d MCF-7 cells. The effect of PEA was due in part to inhibition of AEA degra dation, since treatment of MCF-7 cells with 5 muM PEA caused a similar to 3 0-40 % down-regulation of FAAH expression and activity. However, PEA also e nhanced the cytostatic effect of the cannabinoid receptor agonist HU-210, a lthough less potently than with AEA. PEA did not modify the affinity of lig ands for CB1 or CB2 receptors, and neither did it alter the CB1/CB2-mediate d inhibitory effect of AEA on adenylate cyclase type V, nor the expression of CB1 and CB2 receptors in MCF-7 cells. We suggest that long-term PEA trea tment of cells may positively affect the pharmacological activity of AEA, i n part by inhibiting FAAH expression.