Inhibition of Glioma Growth in Vivo by Selective Activation of the CB2 Cannabinoid Receptor1 Cristina SaÂ´ nchez, 2 MarıÂ´a L. de Ceballos, 2 Teresa GoÂ´ mez del Pulgar, 2 Daniel Rueda, CeÂ´sar Corbacho, Guillermo Velasco, Ismael Galve-Roperh, John W. Huffman, Santiago RamoÂ´ n y Cajal, and Manuel GuzmaÂ´ n 3
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain [C. S., T. G. d. P., D. R., G. V., I. G-R., M. G.];
Neurodegeneration Group, Cajal Institute, CSIC, 28002 Madrid, Spain [M. L. d. C.]; Department of Pathology, ClıÂ´nica Puerta de Hierro, 28035 Madrid, Spain [C. C., S. R. y C.];
and Department of Chemistry, Clemson University, Clemson, South Carolina 29634-1905 [J. W. H.]
[CANCER RESEARCH 61, 5784 –5789, August 1, 2001]
The development of new therapeutic strategies is essential for the management of gliomas, one of the most malignant forms of cancer. We have shown previously that the growth of the rat glioma C6 cell line is inhibited by psychoactive cannabinoids (I. Galve-Roperh et al., Nat. Med., 6: 313–319, 2000). These compounds act on the brain and some other organs through the widely expressed CB1 receptor. By contrast, the other cannabinoid receptor subtype, the CB2 receptor, shows a much more restricted distribution and is absent from normal brain. Here we show that local administration of the selective CB2 agonist JWH-133 at 50 mg/day to Rag-22/2 mice induced a considerable regression of malignant tumors generated by inoculation of C6 glioma cells. The selective involvement of the CB2 receptor in this action was evidenced by: (a) the prevention by the CB2 antagonist SR144528 but not the CB1 antagonist SR141716; (b) the down-regulation of the CB2 receptor but not the CB1 receptor in the tumors; and (c) the absence of typical CB1 -mediated psychotropic side effects. Cannabinoid receptor expression was subsequently examined in biopsies from human astrocytomas. A full 70% (26 of 37) of the human astrocytomas analyzed expressed significant levels of cannabinoid receptors. Of interest, the extent of CB2 receptor expression was directly related with tumor malignancy. In addition, the growth of grade IV human astrocytoma cells in Rag-22/2 mice was completely blocked by JWH-133 administration at 50 mg/day. Experiments carried out with C6 glioma cells in culture evidenced the internalization of the CB2 but not the CB1 receptor upon JWH-133 challenge and showed that selective activation of the CB2 receptor signaled apoptosis via enhanced ceramide synthesis de novo. These results support a therapeutic approach for the treatment of malignant gliomas devoid of psychotropic side effects.
Inhibition of Glioma Growth by Selective Activation of the CB2 Cannabinoid Receptor