3. Umbruch 4.4..2005 - Online Pot

Potential use of cannabimimetics in the treatment of cancer 173
slight, albeit significant, anti-proliferative effect both in vitro and in vivo [30,
32, 117]. This might suggest that non-CB 1-receptor-mediated anti-tumor
effects of endocannabinoids might be unmasked when CB 1 receptors are
blocked. In recent studies [62, 118] the apoptotic effect of anandamide on
glioma cells was suggested to be mediated by another proposed target for this
compound, the transient receptor potential (TRP) vanilloid type 1 (TRPV1)
channel, also known as the VR1 receptor. This protein is a member of the large
family of TRP non-selective cation channels, and is activated by heat, protons,
plant toxins such as capsaicin and resiniferatoxin, and by some other endogenous
arachidonate-derived metabolites (see [63, 64] for reviews). However, the
mechanism through which anandamide induces apoptosis in TRPV1- and
CB 1-expressing cells – that is, whether it involves both CB 1 and TRPV1 receptors,
or only TRPV1 receptors with CB 1 receptors instead playing a protective
role against TRPV1-induced apoptosis – is still controversial, and might
depend on the experimental conditions used for the experiments [65–68]. In
HBCCs, arvanil, a synthetic substance that activates both CB 1 and TRPV1,
exhibits a more potent anti-proliferative activity in vitro than ‘pure’ agonists of
either receptor class, and this action can be attenuated by both CB 1 and TRPV1
antagonists [65]. In glioma cells, anandamide causes apoptosis by acting via
both CB 1 and TRPV1 receptors [66] or only via TRPV1, depending on the cell
culture conditions [62]. In uterine cervix cancer cells in vitro, however, possibly
due to aberrant over-expression of TRPV1, anandamide induces apoptosis
only via activation of these receptors, and activation of CB 1 receptors again
counteracts this effect [67]. Therefore, the actual role of TRPV1 channels in
anandamide-induced inhibition of cancer cell growth (Fig. 1) is still not fully
understood. Furthermore, it remains to be established whether the slight
anti-cancer effect of SR-141716A is due to endocannabinoids being re-directed
towards TRPV1, to counteract the protective action against apoptosis exerted
by CB 1 under certain conditions, or to other, entirely unrelated and
as-yet-identified, mechanisms of action of the CB 1 antagonist. Vanilloid compounds
themselves have been shown to inhibit the proliferation and induce
apoptosis of both cancer and non-transformed cells in vitro by acting via both
TRPV1-and non-TRPV1-mediated mechanisms [68–70], and palmitoylethanolamide
was found to enhance the antiproliferative effect on HBCCs
not only of anandamide and other CB 1 agonists, but also of vanilloids [60].
Therefore, one could envisage the use of this compound, co-administered with
either met-fluoro-anandamide or capsaicin derivatives, to lower the threshold
of the anti-tumor effects of these compounds to doses that do not exhibit either
undesired psychotropic activity or toxicity to healthy cells, respectively.
Plant cannabinoids such as cannabidiol, on the one hand, and ∆ 9 -THC and
cannabinol, on the other, were shown to activate TRPV1 receptors [71] and the
ANKTM1 channel (another member of the TRP family of proteins [72]),
respectively. In fact, Cannabis components with little or no activity on
cannabinoid CB 1 and CB 2 receptors have been shown in the past to exhibit
anti-neoplastic activity in vitro [73]. Cannabidiol has anti-tumor effects on