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Inhibition of Glioma Growth in Vivo by Selective Activation of
the CB2 Cannabinoid Receptor
Cristina Sánchez, María
L. de Ceballos, Teresa Gómez del
Pulgar, Daniel Rueda, César
Corbacho, Guillermo Velasco, Ismael Galve-Roperh,
John W. Huffman, Santiago Ramón y Cajal and Manuel
Guzmán
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, Clínica 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.].
[M. G.]: To whom requests for reprints should be addressed, at Department of
Biochemistry and Molecular Biology I, School of Biology, Complutense
University, 28040 Madrid, Spain. Phone: 34-913944668; Fax:
34-913944672; E-mail: mgp@bbm1.ucm.es.
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 µg/day to Rag-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-2-/- mice was
completely blocked by JWH-133 administration at 50 µg/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.
© 2001 American
Association for Cancer Research
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