The Endogenous Cannabinoid Anandamide Inhibits Human Breast Cancer Cell Proliferation

Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8375-80. doi: 10.1073/pnas.95.14.8375.

Abstract

Anandamide was the first brain metabolite shown to act as a ligand of "central" CB1 cannabinoid receptors. Here we report that the endogenous cannabinoid potently and selectively inhibits the proliferation of human breast cancer cells in vitro. Anandamide dose-dependently inhibited the proliferation of MCF-7 and EFM-19 cells with IC50 values between 0.5 and 1.5 microM and 83-92% maximal inhibition at 5-10 microM. The proliferation of several other nonmammary tumoral cell lines was not affected by 10 microM anandamide. The anti-proliferative effect of anandamide was not due to toxicity or to apoptosis of cells but was accompanied by a reduction of cells in the S phase of the cell cycle. A stable analogue of anandamide (R)-methanandamide, another endogenous cannabinoid, 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 [3H]CP 55, 940 to EFM-19 membranes with an order of potency identical to that observed for the inhibition of EFM-19 cell proliferation. Moreover, anandamide cytostatic effect was inhibited by the selective CB1 receptor antagonist SR 141716A. Cell proliferation was arrested by a prolactin mAb and enhanced by exogenous human prolactin, whose mitogenic action was reverted by very low (0.1-0.5 microM) doses of anandamide. Anandamide suppressed the levels 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 expression 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonic Acids / pharmacology*
  • Arachidonic Acids / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology*
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channel Blockers / therapeutic use
  • Cannabinoids / pharmacology
  • Cannabinoids / therapeutic use
  • Cell Division / drug effects*
  • Dose-Response Relationship, Drug
  • Endocannabinoids
  • Female
  • Humans
  • Polyunsaturated Alkamides
  • Receptors, Cannabinoid
  • Receptors, Drug / agonists
  • Tumor Cells, Cultured

Substances

  • Arachidonic Acids
  • Calcium Channel Blockers
  • Cannabinoids
  • Endocannabinoids
  • Polyunsaturated Alkamides
  • Receptors, Cannabinoid
  • Receptors, Drug
  • anandamide