628 M. Guzmán
differently in tumour and non-tumour cells. Regarding immune cells, cannabi-
noids affect proliferation and survival in a complex and still obscure manner that
depends on the experimental setting. The findings reviewed here might set the
basis for the use of cannabinoids in the treatment of cancer and neurodegenerative
diseases.
KeywordsCell death · Apoptosis · Cell proliferation · Cancer · Neuroprotection
1
Cannabinoid Signalling Pathways and Cell Viability
Cannabinoids, the active components ofCannabis sativaand their derivatives, act
inorganismsbymimickingendogenoussubstances—theendocannabinoidsanan-
damide and 2-arachidonoylglycerol—that bind to and activate specific cannabi-
noid receptors. So far, two cannabinoid-specific Gi/oprotein-coupled receptors,
CB 1 (Matsuda et al. 1990) and CB 2 (Munro et al. 1993), have been cloned and char-
acterised from mammalian tissues. Most of the effects of cannabinoids rely on CB 1
receptor activation. This receptor is particularly abundant in discrete areas of the
brain, but is also expressed in peripheral nerve terminals and various extra-neural
sites such as testis, eye, vascular endothelium and spleen. In contrast, the CB 2
receptor is almost exclusively present in the immune system (Howlett et al. 2002).
Beforetheirspecificreceptorswereidentified,itwasalreadyknownthatcannabi-
noids inhibit adenylyl cyclase (AC) with the consequent decrease in intracellular
cyclic adenosine monophosphate (cAMP) levels (Howlett 1984). The CB 1 receptor
also exerts modulation of ion channels, inducing for example inhibition of N- and
P/Q-type voltage-sensitive Ca2+channels (VSCC) and activation of rectifying K+
channels. These two effects may be responsible for the inhibition of the release of
glutamate and other neurotransmitters by blunting membrane depolarisation and
exocytosis (Piomelli 2003).
Besides these well-established cannabinoid receptor-coupled signalling events,
cannabinoid receptors also modulate several signalling pathways that are more
directly involved in the control of cell proliferation and survival (Table 1). Thus,
cannabinoid receptors are coupled to activation of extracellular signal-regulated
kinase (ERK) (Bouaboula et al. 1995, 1996), c-Jun N-terminal kinase (JNK) and
p38 mitogen-activated protein kinase (MAPK) (Liu et al. 2000; Rueda et al. 2000),
and phosphatidylinositol 3-kinase (PI-3-K)/Akt (Gómez del Pulgar et al. 2000).
Activated Akt can phosphorylate and inhibit nuclear translocation of Forkhead
transcription factors, thereby preventing the expression of pro-apoptotic proteins
(Samson et al. 2003). The negative coupling of cannabinoid receptors to ERK
(Rueda et al. 2002) and Akt (Gómez del Pulgar et al. 2002b) has also been reported.
Cannabinoids modulate sphingolipid-metabolising pathways by inducing sph-
ingomyelin breakdown and increasing acutely the levels of ceramide (Sánchez et al.
1998b; Galve-Roperh et al. 2000), a lipid second messenger that can induce apop-
tosis and cell cycle arrest. This effect is cannabinoid receptor-dependent but Gi/o
protein-independent, and seems to involve the participation of the adaptor pro-