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such as the testis, eye and vascular endothelium, as well as in many epithelial
cells. CB 2 receptors are mostly confined to immune tissues and seem to underlie
the immune-suppressant actions of ∆ 9 -THC [6]. Both CB 1 and CB 2 receptors
are expressed from the early stages of fertilized oocyte development [8],
and CB 1 expression in the developing brain is significantly different from that
observed in the adult brain [9]. Several other plant cannabinoids, with little or
no psychoactive action, have been identified and their possible therapeutic
actions investigated. In particular, cannabidiol [10] appears as a promising therapeutic
tool, even though its sites of action are not yet well understood.
The endogenous cannabinoid receptor ligands (endocannabinoids) identified
so far are all derivatives (amides, esters, ethers) of long-chain polyunsaturated
fatty acids, and exhibit varying selectivity for the two cannabinoid
receptors [7] as well as for other molecular targets [5]. The two best-studied
endocannabinoids are anandamide (N-arachidonoylethanolamine) and
2-arachidonoyl glycerol (2-AG) [11–13], and appear to be ubiquitous in mammalian
tissues. Endocannabinoids, with their receptors [14, 15] and specific
processes of ligand synthesis [16, 17], cellular uptake [16, 18] and degradation
[19, 20], constitute the so-called endocannabinoid system.
The previous knowledge of ∆ 9 -THC pharmacology [21] and, most importantly,
recent studies carried out by using multiple pharmacological, biochemical,
analytical and genetic approaches [22], have revealed several possible
functions of endocannabinoid signaling under both physiological and pathological
conditions. Endocannabinoids have been proposed to act as retrograde
messengers [23] being released from the post-synaptic cell following its depolarization,
to then act back on CB 1 on pre-synaptic neurons to inhibit neurotrasmitter
release. Due to their chemical nature as lipophilic compounds, and
their peculiar biosynthetic mechanisms, endocannabinoids appear to act as
local mediators in an autocrine and/or paracrine manner, and their modulatory
activities on proteins and nuclear factors involved in cell proliferation, differentiation
and apoptosis suggest that the endocannabinoid signaling system is
involved, inter alia, in the control of cell survival, proliferation, transformation
or death [24].
The anti-neoplastic activity of ∆ 9 -THC and its analogs was first observed in
the early 1970s, when neither cannabinoid receptors nor endocannabinoids
had yet been discovered. Although these observations were of potential interest,
no in-depth investigations were performed on this topic until 7 years ago,
when the effects of plant, synthetic and endogenous cannabinoids on cancer
cell proliferation and apoptosis started to be revisited. By contrast, the beneficial
effects of cannabinoids on some cancer-related disorders, such as emesis,
nausea, depression, muscle tension, insomnia, chronic pain and appetite suppression,
have been in part exploited pharmaceutically, since oral ∆ 9 -THC
(dronabinol ® , marinol ® ) can be prescribed legally in the USA for the treatment
of nausea and emesis and as an appetite-stimulating drug for cancer patients
undergoing chemotherapy and patients with AIDS, respectively. The results of
a large body of recent studies now suggest that targeting the endocannabinoid