Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis.
Stimulation of cannabinoid CB1 receptors by 2-methyl-arachidonyl-2'-fluoro-ethylamide (Met-F-AEA) inhibits the growth of a rat thyroid cancer cell-derived tumor in athymic mice by inhibiting the activity of the oncogene product p21ras. Here we report that Met-F-AEA also blocks the growth of tumors previously induced in nude mice by the s.c. injection of the same rat thyroid carcinoma cells. Met-F-AEA significantly inhibited, in tumors as well as transformed cells, the expression of the vascular endothelial growth factor, an angiogenetic factor known to be up-regulated by p21ras, as well as of one of its receptors, flt-1/VEGFR-1. The levels of the cyclin-dependent kinase inhibitor p27(kip1), which is down-regulated by p21ras, were instead increased by Met-F-AEA. All these effects were antagonized by the selective CB1 receptor antagonist SR141716A. Met-F-AEA inhibited in vitro the growth of a metastasis-derived thyroid cancer cell line more potently than a primary cancer cell line. Therefore, the hypothesis that CB1 receptor stimulation interferes not only with angiogenesis but also with metastatic processes was tested in a widely used model of metastatic infiltration in vivo, the Lewis lung carcinoma (3LL) in C57Bl/6 mice. Three weeks from the paw injection of 3LL cells, Met-F-AEA reduced significantly the number of metastatic nodes, in a way antagonized by SR141716A. Our findings indicate that CB1 receptor agonists might be used therapeutically to retard tumor growth in vivo by inhibiting at once tumor growth, angiogenesis, and metastasis.
Portella
Giuseppe
G
Endocannabinoid Research Group, Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, and Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Università di Napoli Federico II, Italy.
Laezza
Chiara
C
Laccetti
Paolo
P
De Petrocellis
Luciano
L
Di Marzo
Vincenzo
V
Bifulco
Maurizio
M
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001095:Arachidonic Acids / Q000627:therapeutic use; D002186:Cannabinoids / Q000627:therapeutic use; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism*; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000473:pathology; D014407:Tumor Cells, Cultured
C443759:2-methylarachidonyl-2'-fluoroethylamide; D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D002186:Cannabinoids; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug