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Inhibition of skin tumor growth and angiogenesis in vivo by activation of
cannabinoid receptors
M. Llanos Casanova, Cristina Blázquez, Jesús
Martínez-Palacio, Concepción Villanueva, M. Jesús
Fernández-Aceñero, John W. Huffman, José L. Jorcano
and Manuel Guzmán
Project on Cellular and Molecular Biology and Gene Therapy,
Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas,
Madrid, Spain [M.L.C., J.M.-P., J.L.J.]; Department of Biochemistry and
Molecular Biology I, School of Biology, Complutense University, Madrid, Spain
[C.B., M.G.]; Department of Pathology, Hospital General de Móstoles, Madrid,
Spain [C.V., M.J.F.-A.]; Department of Chemistry, Clemson University, Clemson,
South Carolina, USA [J.W.H.]. Address correspondence to: Manuel Guzmán, 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.
Received for publication June 7, 2002, and accepted in revised form November 19,
2002.
Nonmelanoma skin cancer is one of the most common malignancies in
humans.
Different therapeutic strategies for the treatment of these
tumors are currently being investigated.
Given the growth-inhibiting
effects of cannabinoids on gliomas and the wide tissue distribution
of the two subtypes of cannabinoid receptors (CB1 and CB2),
we studied the potential utility of these compounds in anti–skin
tumor therapy.
Here we show that the CB1 and the CB2
receptor are expressed in normal skin and skin tumors of mice and
humans.
In cell culture experiments pharmacological activation of
cannabinoid receptors induced the apoptotic death of tumorigenic
epidermal cells, whereas the viability of nontransformed epidermal
cells remained unaffected.
Local administration of the mixed CB1/CB2
agonist WIN-55,212-2 or the selective CB2 agonist JWH-133
induced a considerable growth inhibition of malignant tumors
generated by inoculation of epidermal tumor cells into nude mice.
Cannabinoid-treated tumors showed an increased number of apoptotic
cells.
This was accompanied by impairment of tumor vascularization,
as determined by altered blood vessel morphology and decreased
expression of proangiogenic factors (VEGF, placental growth factor,
and angiopoietin 2).
Abrogation of EGF-R function was also observed
in cannabinoid-treated tumors.
These results support a new therapeutic
approach for the treatment of skin tumors.
Copyright ©2003 by the American Society for Clinical
Investigation
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