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Figure 1. Possible ways for endocannabinoids to inhibit cancer growth. Stimulation of cannabinoid
receptors by endocannabinoids can interfere with tumor growth in two possible ways: (1) by stopping
the cancer cell cycle (anti-proliferative or anti-mitogenic effect) via inhibition of the activity of p21 ras
or of the expression of growth factors and/or of their receptors; (2) by promoting cancer cell apoptosis.
The intracellular pathways mediating these two effects are schematically depicted in Figure 2.
Furthermore, some endocannabinoids, like anandamide or N-arachidonoyldopamine [115], can also
cause cancer cell apoptosis by both activating CB 1 receptors and gating vanilloid TRPV1 receptors.
The latter effect causes a strong Ca 2+ influx that can then lead to apoptosis and in some cases also to
cell toxicity. AC, adenylate cyclase; AEA, N-arachidonoylethanolamine (anandamide); CBR,
cannabinoid receptor; ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein
kinase kinase; PKA, protein kinase A; TRPV1, transient potential receptor vanilloid type 1 channel.
Substances that activate CB 1 receptors might also exert more general
anti-tumor as well as anti-angiogenic effects by interfering with the expression
of other growth and mitogenic factors (Fig. 2). CB 1 receptor activation also
induces cell-cycle arrest at the G 0/G 1–S transition in thyroid epithelioma cells
(KiMol Cells) obtained from the transformation of rat thyroid epithelial cells
with the K-ras oncogene. Furthermore, repeated intra-tumor administration of
a very low and non-psychotropic dose of a metabolically stable and more
potent CB 1 receptor ligand, met-fluoro-anandamide, inhibits the growth of
tumors induced in nude mice by injection of these cells [33]. This effect is
accompanied by a strong reduction of the activity of the K-ras oncogene protein
product, p21 ras . It was also shown that the expression of CB 1 receptors is
regulated in healthy and transformed thyroid cells (as well as in tumors derived
from these latter cells) in opposite ways following treatment with met-fluo-