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

Abstract

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.

• Authors: M Bifulco, C Laezza, G Portella, M Vitale, P Orlando, L De Petrocellis, V Di Marzo
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 15 Issue 14 Pg. 2745-7 (Dec 2001) ISSN: 1530-6860 [Electronic] United States
• PMID: 11687506 (Publication Type: Journal Article)

Chemical References

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

Topics

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