3. Umbruch 4.4..2005 - Online Pot

172 L. De Petrocellis et al.
a possible role of the endocannabinoid system in the tonic suppression of the
growth and spread of some tumors. In support of this hypothesis it was found
that alterations also of anandamide or 2-AG levels occur in many tumors as
compared to the corresponding healthy tissues ([53–55], see also [56]). In particular,
an enhancement of endocannabinoid levels was observed in human
breast cancers and prostate carcinomas ([55], see also [56]), in human pituitary
tumors [53] and in human colorectal carcinomas [57]. In addition, human colorectal
cancer Caco-2 cells loose their capability to respond to cannabinoid
receptor agonists, and make less endocannabinoids, when they differentiate
into non-malignant cells [57]. As cells from these tumors all respond to
cannabinoids with inhibition of proliferation, or by entering apoptosis, it was
suggested that endocannabinoids are endogenously over-produced in malignant
tissues and cells, and cannabinoid receptors (and other endocannabinoid
molecular targets) are subsequently over-stimulated, in the attempt to counteract
cancer growth and spread. So far, evidence for this hypothesis has been
obtained mostly in vitro. Anandamide and its congeners are produced by
HBCCs, and a substance that elevates the levels of anandamide in these cells
also inhibits cell proliferation [58], suggesting that synthetic compounds that
selectively inhibit endocannabinoid degradation might also be used to inhibit
cancer growth. In fact, two selective and specific inhibitors of endocannabinoid
inactivation were recently found to inhibit Caco-2 cell proliferation in a
CB 1-receptor-mediated manner and through elevation of cell endocannabinoid
levels [57]. Palmitoylethanolamide, an anandamide congener that is synthesized
in higher amounts than anandamide in all tumor cells analysed so far,
inhibits the degradation of endocannabinoids in HBBCs, and may act as an
endogenous enhancer of the tumor-suppressing activity of this endocannabinoid,
whether this is exerted via CB 1 [59] or other ([60] and see below) receptors.
Data from our laboratories indicate that this endogenous control of cancer
growth by endocannabinoids can also occur in vivo, as two selective
inhibitors of anandamide and 2-AG inactivation induce a strong CB 1-mediated
inhibition of rat thyroid epithelioma growth in athymic mice by enhancing
the tumor levels of these two compounds [117]. Furthermore, it was recently
shown that inhibition of 2-AG degradation and biosynthesis can inhibit and
enhance, respectively, the invasion of human prostate cancer cells in vitro
[120].
Non-CB 1/-CB 2 receptors are also involved in (endo)cannabinoid
anti-tumor actions
An ever-increasing number of reports (reviewed recently by Pertwee [61]) suggests
that endocannabinoids might exert their biological effects also through
non-CB 1/-CB 2 receptors. Regarding the inhibition of cancer growth, experiments
carried out in our laboratories have shown that, rather than favoring cancer
cell proliferation, the CB 1-selective antagonist SR-141716A causes a