Inhibition of glioma growth in vivo by selective activation of the CB2 cannabinoid receptor

The development of new therapeutic strategies is essential for the manageme nt of gliomas, one of the most malignant forms of cancer. We have shown pre viously that the growth of the rat glioma C6 cell line is inhibited by psyc hoactive 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 mug/day to Rag-2(-/-) mice induced a considerabl e regression of malignant tumors generated by inoculation of C6 glioma cell s. The selective involvement of the CB2 receptor in this action was evidenc ed by: (a) the prevention by the CB2 antagonist SR144528 but not the CB1 an tagonist SR141716; (b) the down-regulation of the CB2 receptor but not the CB1 receptor in the tumors; and (c) the absence of typical CBI-mediated psy chotropic side effects. Cannabinoid receptor expression was subsequently ex amined in biopsies from human astrocytomas. A full 70% (26 of 37) of the hu man astrocytomas analyzed expressed significant levels of cannabinoid recep tors. Of interest, the extent of CB1 receptor expression was directly relat ed with tumor malignancy. In addition, the growth of grade IV human astrocy toma cells in Rag-2(-/-) mice was completely blocked by JWH-133 administrat ion at 50 mug/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 sign aled apoptosis via enhanced ceramide synthesis de novo. These results suppo rt a therapeutic approach for the treatment of malignant gliomas devoid of psychotropic side effects.