Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth

FASEB J. 2001 Dec;15(14):2745-7. doi: 10.1096/fj.01-0320fje. Epub 2001 Oct 29.


We investigated the effect of 2-methyl-arachidonyl-2'-fluoro-ethylamide (Met-F-AEA), a stable analog of the endocannabinoid anandamide, on a rat thyroid epithelial cell line (FRTL-5) transformed by the K-ras oncogene, and on epithelial tumors derived from these cells. Met-F-AEA effect in vivo was evaluated in a nude mouse xenograft model, where K-ras-transformed (KiMol) cells were implanted subcutaneously. Met-F-AEA (0.5 mg/kg/dose) induced a drastic reduction in tumor volume. This effect was inhibited by the CB1 receptor antagonist SR141716A (0.7 mg/kg/dose) and was accompanied by a strong reduction of K-ras activity. Accordingly, KiMol cells and tumors express CB1 receptors. Met-F-AEA inhibited (IC50 ~5 mM) the proliferation in vitro and the transition to the S phase of KiMol cells and it reduced K-ras activity; these effects were antagonized by SR141716A. Met-F-AEA cytostatic action was significantly smaller in nontransformed FRTL-5 cells than in KiMol cells. Met-F-AEA treatment exerted opposite effects on the expression of CB1 receptors in KiMol and FRTL-5 cells, with a strong up-regulation in the former case and a suppression in nontransformed cells. The data suggest that: 1) Met-F-AEA inhibits ras oncogene-dependent tumor growth in vivo through CB1 cannabinoid receptors; and 2) responsiveness of FRTL-5 cells to endocannabinoids depends on whether or not they are transformed by K-ras.

MeSH terms

  • Animals
  • Arachidonic Acids / chemistry
  • Arachidonic Acids / pharmacology
  • Blotting, Western
  • Cannabinoid Receptor Modulators
  • Cannabinoids / metabolism
  • Cannabinoids / pharmacology*
  • Cell Cycle / drug effects
  • Cell Division / drug effects*
  • Cell Line
  • Cell Line, Transformed
  • Dose-Response Relationship, Drug
  • Endocannabinoids
  • Genes, ras / genetics
  • Genes, ras / physiology*
  • Mice
  • Mice, Nude
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / prevention & control*
  • Piperidines / pharmacology
  • Polyunsaturated Alkamides
  • Pyrazoles / pharmacology
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Cannabinoid
  • Receptors, Drug / antagonists & inhibitors
  • Receptors, Drug / genetics
  • Receptors, Drug / metabolism
  • Rimonabant
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / prevention & control
  • Xenograft Model Antitumor Assays


  • 2-methylarachidonyl-2'-fluoroethylamide
  • Arachidonic Acids
  • Cannabinoid Receptor Modulators
  • Cannabinoids
  • Endocannabinoids
  • Piperidines
  • Polyunsaturated Alkamides
  • Pyrazoles
  • RNA, Messenger
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Rimonabant
  • anandamide