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 CB(1) receptor. By contrast, the other
cannabinoid receptor subtype, the CB(2) receptor, shows a much more restricted distribution and is absent from normal brain. Here we show that local administration of the selective CB(2) agonist
JWH-133 at 50 microg/day to Rag-2(-/-) mice induced a considerable regression of malignant
tumors generated by inoculation of C6
glioma cells. The selective involvement of the CB(2) receptor in this action was evidenced by: (a) the prevention by the CB(2) antagonist
SR144528 but not the CB(1) antagonist
SR141716; (b) the down-regulation of the CB(2) receptor but not the CB(1) receptor in the
tumors; and (c) the absence of typical CB(1)-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 CB(2) receptor expression was directly related with
tumor malignancy. In addition, the growth of grade IV human
astrocytoma cells in Rag-2(-/-) mice was completely blocked by
JWH-133 administration at 50 microg/day. Experiments carried out with C6
glioma cells in culture evidenced the internalization of the CB(2) but not the CB(1) receptor upon
JWH-133 challenge and showed that selective activation of the CB(2) 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.