THE ENDOGENOUS CANNABINOID ANANDAMIDE INHIBITS HUMAN BREAST-CANCER CELL-PROLIFERATION

Anandamide was the first brain metabolite shown to act as a ligand of ''central'' CB1 cannabinoid receptors, Here we report that the endogen ous cannabinoid potently and selectively inhibits the proliferation of human breast cancer cells in vitro, Anandamide dose-dependently inhib ited the proliferation of MCF-7 and EFM-19 cells with IC50 values betw een 0.5 and 1.5 mu M and 83-92% maximal inhibition at 5-10 mu M. The p roliferation of several other nonmammary tumoral cell lines was not af fected by 10 ELM anandamide, The anti-proliferative effect of anandami de was not due to toxicity or to apoptosis of cells but was accompanie d by a reduction of cells in the S phase of the cell cycle. A stable a nalogue of anandamide (R)-methanandamide, another endogenous cannabino id, 2-arachidonoylglycerol, and the synthetic cannabinoid HU-210 also inhibited EFM-19 cell proliferation, whereas arachidonic acid was much less effective. These cannabimimetic substances displaced the binding of the selective cannabinoid agonist [H-3] CP 55,940 to EFM-19 membra nes with an order of potency identical to that observed for the inhibi tion of EFM-19 cell proliferation. Moreover, anandamide cytostatic eff ect was inhibited by the selective CB1 receptor antagonist SR 141716A, Cell proliferation was arrested by a prolactin mAb and enhanced by ex ogenous human prolactin, whose mitogenic action was reverted by very l ow (0.1-0.5 mu M) doses of anandamide, Anandamide suppressed the level s of the long form of the prolactin receptor in both EFM-19 and MCF-7 cells, as well as a typical prolactin-induced response, i.e., the expr ession of the breast cancer cell susceptibility gene brca1, These data suggest that anandamide blocks human breast cancer cell proliferation through CB1-like receptor-mediated inhibition of endogenous prolactin action at the level of prolactin receptor.