Effects on Cell Viability 6375
Potential Therapeutic Implications
Many studies have dealt with the antiproliferative effect of cannabinoids on differ-
ent transformed cells. The case of gliomas may be of particular interest because
they are one of the most malignant forms of cancer, resulting in the death of
affected patients within months after diagnosis. One of the alternative therapeu-
tic approaches for gliomas might be the use of cannabinoid agonists, since these
compounds induce apoptosis in vitro and inhibition of tumour angiogenesis and
growth without significant collateral effects in vivo (Galve-Roperh et al. 2000;
Sánchez et al. 2001a). Based on these observations, a phase I/II clinical trial is
currently investigating the effect of local administration of THC on the growth
of recurrent glioblastoma multiforme (Guzmán 2003). It would be desirable that
other trials on this and other types of tumours are initiated to determine whether
cannabinoids can be used as antitumoural agents.
Different neurological and neurodegenerative diseases are accompanied by ex-
citotoxicity, oxidative stress, Ca2+imbalance and/or inflammatory responses, lead-
ing to progressive neuronal death. As discussed above, cannabinoids may interfere
with these processes, which sets the basis for a potential therapeutic utility of
these compounds. Laboratory research has shown that this may be the case with,
for example, Huntington’s disease (Lastres-Becker et al. 2003), multiple sclerosis
(Baker et al. 2000) and brain trauma (Panikashvili et al. 2001). In addition, the
existence of an inhibitory loop by which endocannabinoids blunt dopaminergic
control of movement (Giuffrida et al. 1999) point to the potential use of CB 1 an-
tagonists for the management of Parkinson’s disease (Piomelli 2003) and of CB 1
agonists as agents for preventing symptoms of Tourette’s disease (Muller-Vahl
2003). A recent large-scale phase III clinical trial has tested the effect of THC
alone or in combination with other cannabinoids for the treatment of spasticity
and other muscle-debilitating symptoms of multiple sclerosis, yielding conflict-
ing but encouraging results (Zajicek et al. 2003). Phase III clinical trials are also
being conducted with the non-psychoactive cannabinoid HU-211 (dexanabinol),
a non-competitiveN-methyl-d-aspartate receptor antagonist (Feigenbaum et al.
1989), for the treatment of severe head trauma (Knoller et al. 2002). This compound
reduces the inflammatory response after closed-head injury or lipopolysaccharide-
induced septic shock both in vivo and in vitro, and prevents tremor, seizures and
lethality in laboratory animals (Gallily et al. 1997). Ongoing and future clinical
trials should determine the usefulness of cannabinoids as therapeutic agents for
the management of neurological and neurodegenerative diseases.
As reviewed here, cannabinoids may lead to opposite effects on the cell sur-
vival/death decision. For example, in the case of neural cells, cannabinoids may kill
tumour cells and protect their non-transformed counterparts from death (Guzmán
2003) (Fig. 1). It is conceivable that different experimental factors may account for
this “yin-yang” action, for example : (1) cannabinoid neuroprotection is usually
more evident in whole-animal than in cultured-neuron models, which may result
from their aforementioned impact on various brain cell types (neurons, astroglia,
oligodendroglia, microglia, vascular endothelium); (2) cannabinoids may exert