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Research Article

The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation

Luciano De Petrocellis, Dominique Melck, Antonella Palmisano, Tiziana Bisogno, Chiara Laezza, Maurizio Bifulco, and Vincenzo Di Marzo
PNAS July 7, 1998 95 (14) 8375-8380; https://doi.org/10.1073/pnas.95.14.8375
Luciano De Petrocellis
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Dominique Melck
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Antonella Palmisano
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Tiziana Bisogno
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Chiara Laezza
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Maurizio Bifulco
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Vincenzo Di Marzo
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  1. Communicated by Rita Levi-Montalcini, Institute of Neurobiology, Consiglio Nazionale delle Ricerche, Rome, Italy (received for review March 6, 1998)

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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 μM and 83–92% maximal inhibition at 5–10 μM. The proliferation of several other nonmammary tumoral cell lines was not affected by 10 μM 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 μM) 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.

Footnotes

    • ↵* L.D.P. & D.M. contributed equally to this work.

    • ↵‖ To whom reprint requests should be addressed. e-mail: VDM{at}TRINC.ICMIB.NA.CNR.IT.

  • ABBREVIATION

    HBC,
    human breast cancer
    • Received March 6, 1998.
    • Accepted April 29, 1998.
    • Copyright © 1998, The National Academy of Sciences
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    The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation
    Luciano De Petrocellis, Dominique Melck, Antonella Palmisano, Tiziana Bisogno, Chiara Laezza, Maurizio Bifulco, Vincenzo Di Marzo
    Proceedings of the National Academy of Sciences Jul 1998, 95 (14) 8375-8380; DOI: 10.1073/pnas.95.14.8375

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    The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation
    Luciano De Petrocellis, Dominique Melck, Antonella Palmisano, Tiziana Bisogno, Chiara Laezza, Maurizio Bifulco, Vincenzo Di Marzo
    Proceedings of the National Academy of Sciences Jul 1998, 95 (14) 8375-8380; DOI: 10.1073/pnas.95.14.8375
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