Cannabinoids recently have been shown to control the cell survival/death decision. Thus, cannabinoids induce growth arrest or apoptosis in a number of transformed neural and non-neural cells in culture. In addition, cannabinoid administration induces regression of malignant gliomas in rodents by a mechanism that may involve sustained ceramide generation and extracellular signal-regulated kinase activation. Regarding immune cells, low doses of cannabinoids may enhance proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis.
Gliomas
Various cannabinoids have been shown to induce the death of glioma, astrocytoma, neuroblastoma and pheochromocytoma cells in culture, and, most interestingly, the regression of malignant gliomas in vivo.
Thus rats when treated intratumourally with THC for 1 week, survived significantly longer than untreated animals.
Moreover, a complete eradication of the tumours was evidenced in 20–35% of the treated animals.
Recent studies show that both the CB1 and CB2 receptor are involvement of in cannabinoid- induced apoptosis which could provide the basis for the management of gliomas without psychotropic side-effects.
Mechanism of cannabinoid action
Several signalling pathways have been implicated in cannabinoid-induced apoptosis of transformed neural cells.
The apoptotic death of C6 glioma cells seems to depend on the sustained generation of ceramide.
The increased ceramide levels observed in glioma cells upon cannabinoid challenge would lead to the activation of the ERK cascade mediated by Raf-1.
It is generally accepted that the activation of the ERK cascade leads to cell proliferation. However, recent investigations have begun to define situations in which ERK mediates growth arrest, as well as apoptotic and non-apoptotic death, in many cells, including neural cells.
The data show that the apoptotic action of THC relies on the long-term peak of ceramide generation and ERK activation.
Breast Cancer
The effect of cannabinoids on human breast cancer cell growth has been studied. In particular it has been found a strong antiproliferative action with CB1-mediated mechanism.
Unlike cannabinoid-induced apoptosis of glioma cells, cannabinoid-induced inhibition of breast cancer cell growth does not involve apoptosis, but cell cycle arrest, at the G1/S transition and G2-M.
It has been found a correlation between CB2 expression and histologic grade of the tumors. There was also an association between CB2 expression and other markers of prognostic and predictive value, such as estrogen receptor, progesterone receptor, and ERB2/HER2.
Importantly, no significant CB2 expression was detected in nontumor breast tissue. Taken together, these data might set the bases for a cannabinoid therapy for the management of breast cancer.
Mechanism of cannabinoid action
CB1 receptor activation has been shown to inhibit AC and to activate the Raf-1/ERK cascade.
These two signalling events seem to mediate—at least in part—the antiproliferative action.
Modulation of the synthesis of neurotrophins and their receptors via the
ERK cascade may be an additional factor involved in the control of cell fate by cannabinoids.
It is worth noting that human breast cancer cells produce significant amounts of acylethanolamides.
Other authors have discovered that THC arrests cells in G(2)-M via down-regulation of Cdc2. Of interest, the proliferation pattern of normal human mammary epithelial cells was much less affected by THC.
Prostate Cancer
Expression levels of both cannabinoid receptors, CB1 and CB2, are significantly higher in human prostate cells than in human prostate epithelial and it was discovered that the expression of these receptors correlates with the prognosis of the tumor.
Mixed CB1/CB2 agonist treatment with androgen-responsive resulted in a dose-and time-dependent inhibition of cell growth, blocking of CB1 and CB2 receptors by their antagonists significantly prevented this effect.
The effects are induction of apoptosis, decrease in protein expression of androgen receptor, decrease in intracellular protein of PSA, decrease of vascular endothelial growth factor.
Our results suggest that non-habit-forming cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer.
On the hormonal side is interesting to mention that Delta 9-tetrahydrocannabinol and cannabinol have an anti-androgenic effects associated at least in part, from inhibition of androgen action at the receptor level.
Furthermore Marijuana affects hypothalamic function and it appears that the psychoactive ingredient, THC, is the major compound responsible for this action. It is probable that THC affects these hormones through its ability to alter various neural transmitters.
The THC-induced block of GnRH release results in lowered LH and FSH which is responsible for reduced testosterone production by the Leydig cells of the testis.
Reduced testosterone and FSH may be important in producing the observed changes in sperm production by the seminiferous tubules.
THC appears to depress prolactin, thyroid gland function, and growth hormone while elevating adrenal cortical steroids.
Mechanism of cannabinoid action
Tetrahydrocannabinol appears to induce apoptosis via a receptor-independent manner.
Interestingly the activation of cannabinoid receptors also stimulated the PI3K/Akt pathway with sequential involvement of Raf-1/ERK1/2 and nerve growth factor induction.
Cannabinoids caused inhibition of cell growth and induction of apoptosis with an arrest of the cells in the G0-G1 phase of the cell cycle.
Antiproliferative and apoptotic effects of endogenous cannabinoids anandamide in human prostate cancer were found to be mediated through down-regulation of epidermal growth factor receptor
(EGFR) and accumulation of ceramide.
Interestingly, anandamide analogue ( R )-methanandamide was shown to have a mitogenic effect at very low doses (16).
CB1 receptor activation has been shown to inhibit AC and to activate the Raf-1/ERK cascade.
These two signalling events seem to mediate—at least in part—the antiproliferative action.
Modulation of the synthesis of neurotrophins and their receptors via the
ERK cascade may be an additional factor involved in the control of cell fate by cannabinoids.
Lung Cancer
The research about the use of cannabinoids in lung cancer are quite difficult to interpretate.
SOme studies showed that tetrahydrocannabinol administration accelerate proliferation of lung cancer cells that was probably dependent on EGFR-mediated activation of ERK1/2 as well as PKB/Akt signalling.
Skin Cancer
It was reported that CB1 and the CB2 receptors are expressed in normal skin and skin tumors of mice and humans. In vitro studies showed that activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, without affecting the nontransformed epidermal cells.
Another study showed that activation of these receptors decreased tumor growth, angiogenesis and metastasis of melanomas in mice, and inhibited proliferation via inhibition of Akt pathway and hypophosphorylation of retinoblastoma in melanoma cells.
Another non cancer treatment could be attempted in psoriasis.
Anandamide, an endogenous CB receptor ligand, inhibits epidermal keratinocyte differentiation. Psoriasis is an inflammatory disease also characterised in part by epidermal keratinocyte hyper-proliferation.
Δ-9 tetrahydrocannabinol, cannabidiol, cannabinol and cannabigerol all can inhibit keratinocyte proliferation in a concentration-dependent manner the activity of theses agonists were not blocked by either CB1/CB2 antagonists.
The results indicate that that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis.
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Francesco Licciardi e Matteo Manfredi
