3. Umbruch 4.4..2005 - Online Pot

Potential use of cannabimimetics in the treatment of cancer 171
are functional in the regression of skin carcinomas, which may also rely on the
inhibition of tumor angiogenesis. The blood vessels developed by cannabinoid-treated
carcinomas were in fact small, and the expression of pro-angiogenic
factors was depressed [35]. Once more, ras activation seems to be crucial
in mouse skin carcinoma initiation and angiogenesis in which VEGF plays
a pivotal role [50].
Also in a mouse model of glioma, local administration of a CB 2
receptor-selective agonist inhibits angiogenesis of malignant gliomas as determined
by immunohistochemical and functional analyses [51]. In vitro and in
vivo studies have shown a direct inhibition by cannabinoids of vascular hyperplasia
characteristic of actively growing tumors into a pattern of small, differentiated
and impermeable blood capillaries. This is once more associated with
a decreased expression of VEGF and other vascular pro-angiogenic factors.
Furthermore the activation of cannabinoid receptors inhibited endothelial cell
migration and survival. Interestingly, the expression and activity of matrix
metalloproteinase-2, a proteolytic enzyme that allows tissue remodelling during
angiogenesis and metastasis, was also decreased by cannabinoids [51].
More recently, ∆ 9 -THC was also shown to reduce the expression in gliomas of
the VEGF receptor, VEGFR-2, both in vitro and in vivo, and via blockade of
ceramide biosynthesis [119].
Finally, it was observed that the CB 1-mediated anti-proliferative effect of
met-fluoro-anandamide on thyroid cancer cells was much more efficacious on
metastasis-derived cells than on the primary cancer line, possibly due to an
upregulation of CB 1 receptors in the former cells (see below). Accordingly, in
the Lewis lung carcinoma model of metastatic spreading, met-fluoro-anandamide
was found to interfere efficaciously with the formation of lung
metastatic nodules by acting at CB 1 receptors [37]. The mechanism through
which stimulation of CB 1 receptors can lead to inhibition of the cellular
processes involved in cancer cell metastatic spreading, including cell motility
and adhesion, are currently under investigation in our laboratories. However,
preliminary data on the inhibition of the migration of SW 480 colon carcinoma
cells by anandamide and the selective CB 2 receptor agonist JWH133, via
CB 1- and CB 2-receptor-mediated mechanisms, respectively, have been published
[52]. Furthermore, experiments carried out by using human prostate
cancer cells, also showed that 2-AG can inhibit invasion in vitro only in androgen-independent
cells and via inhibition of cAMP- and protein kinase A-mediated
signaling [120].
The endocannabinoid system attempts to provide protection from the
growth and spread of cancer
The increasing expression of cannabinoid receptors in cancer cells and tissues
observed with their increasing degree of malignancy and invasiveness, for
example in astrocytomas and transformed thyroid cells [33, 38], might suggest