3. Umbruch 4.4..2005 - Online Pot

Potential use of cannabimimetics in the treatment of cancer 167
system might provide a significant contribution to both palliative and curative
cancer therapies.
Cannabinoid receptor stimulation causes inhibition of cancer growth
through multiple intracellular mechanisms and pathways
Based on Cannabis perturbation of the immune response, in vivo studies carried
out in animals in the late 1990s investigated the possibility that marijuana smoking
and long-term ∆ 9 -THC treatment may favor tumor growth. These studies,
however, often produced opposing outcomes. For example, the enhancement of
lung carcinoma was seen [25], and more recently it has been demonstrated that
the treatment of glioma and lung carcinoma cell lines with nanomolar concentrations
of ∆ 9 -THC, comparable with those detected in the serum of patients
after ∆ 9 -THC administration, leads to accelerated cancer cell proliferation
dependent on metalloprotease and epidermal growth factor receptor (EGFR)
activity [26]. While in this study the involvement of cannabinoid receptors was
not investigated, in another recent work low concentrations of ∆ 9 -THC also
stimulated the proliferation of prostate carcinoma cells in vitro, in a
CB 1-/CB 2-mediated manner and androgen receptor-dependent manner [27].
However, Munson and coworkers showed about 30 years ago that ∆ 9 -THC
inhibits lung adenocarcinoma cell growth in vitro and after oral administration
in mice [28], and a recent 2-year chronic administration study with high ∆ 9 -THC
doses revealed a reduction of the spontaneous onset of hormone-dependent
tumors in particular [29]. Experiments carried out in vitro seem to go more often
in the direction of an anti-proliferative property of CB 1 and CB 2 receptor agonists
(Fig. 1). For example, it was found that 4–5-day treatment of human breast
cancer cell (HBCC) lines with sub-micromolar concentrations of endocannabinoids
results in complete blockade of their proliferation [30]. CB 1 activation
blocks the cell cycle at the G 0/G 1–S transition via the inhibition of adenylate
cyclase and the cAMP/protein kinase A pathway. Protein kinase A phosphorylates
and inhibits Raf1, and therefore anandamide, by preventing the inhibition
of Raf1, induces the sustained activation of the Raf1/mitogen-activated protein
kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling cascade
[31]. These signaling events result in the inhibition of the expression of the
long form of the receptor for endogenous prolactin [30], a hormone that HBCCs
in culture use as an autocrine growth factor. In fact, agents activating the CB 1
receptor via the same mechanism also counteract the proliferation of human
prostate cancer cells when induced by exogenous prolactin [32]. Indeed, both
human breast and prostate cancer cells express high levels of CB 1 receptors that
had never been detected previously in the corresponding healthy tissues. HBCCs
also respond to nerve growth factor (NGF) by proliferating more rapidly, and
2-day treatment of HBCCs with CB 1 receptor agonists suppresses the levels of
trk proteins, one of the two known types of NGF receptor, thus resulting in the
inhibition of NGF-induced proliferation [32].