Cannabinoids

Effects on Cell Viability 629

Table 1.Control by cannabinoids of intracellular signalling pathways that may affect cell proliferation and
survival

Signalling pathway Cannabinoid effect Effect on cell number

Ceramide generation Activation Decrease

ERK Activation (sustained) Decrease

Activation (acute) Increase?

PI-3-K/Akt Activation Increase

Inhibition Decrease

JNK and p38 MAPK Activation Decrease

cAMP/PKA Inhibition Decrease?

cAMP, cyclic adenosine monophosphate; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal
kinase; MAPK, mitogen-activated protein kinase; PI-3-K, phosphoinositide 3-kinase; PKA, protein kinase A.

tein FAN (factor associated with neutral sphingomyelinase activation) (Sánchez et
al. 2001b). Cannabinoid receptor activation can also generate a sustained peak of
ceramide accumulation via enhanced synthesis de novo that plays an important
role in the induction of apoptosis (Galve-Roperh et al. 2000; Gómez del Pulgar et
al. 2002b).

2

Tumour Cells

2.1

Antitumoural Effect

A number of plant-derived [for example,∆^9 -tetrahydrocannabinol (THC) and

cannabidiol], synthetic (for example, WIN 55,212-2 and HU-210) and endogenous
cannabinoids (for example, anandamide and 2-arachidonoylglycerol) have been
shown to exert antiproliferative actions on a wide spectrum of tumour cells in
culture (Guzmán 2003; Jones and Howl 2003). More importantly, cannabinoid ad-
ministration to nude mice curbs the growth of various types of tumour xenografts,
including lung carcinoma (Munson et al. 1975), glioma (Galve-Roperh et al. 2000),
thyroid epithelioma (Bifulco et al. 2001), lymphoma (McKallip et al. 2002a) and
skin carcinoma (Casanova et al. 2003).
The antitumoural action of cannabinoids may be exemplified by gliomas. Initial
experiments in cultured glioma cells showed that incubation with cannabinoids in-
duces cell death by an apoptotic mechanism (Sánchez et al. 1998a). Further studies
with animal models showed that local administration of THC or WIN 55,212-2 re-
duced the size of tumours generated by intracranial inoculation of C6 glioma cells
in rats, leading to complete eradication of gliomas and subsequent survival in one
third of the treated rats (Galve-Roperh et al. 2000). Additional studies employed
tumour xenografts generated by subcutaneous injection of glioma cells in the flank
of immune-deficient mice. Local administration of THC, WIN 55,212-2, the selec-
tive CB 2 agonist JWH-133 or cannabidiol decreased the growth of tumours derived