Cannabis
Substance Abuse

CANNABINOID ANTICANCER ACTION: A NEW THERAPEUTIC STRATEGIES?

INTRODUCTION

Δ9-Tetrahydrocannabinol (THC), the main active component of marijuana, exerts a wide variety of biological effects by mimicking endogenous substances — the endocannabinoids — that bind to and activate specific cannabinoid receptors. One of the most exciting areas of research in the cannabinoid field is the study of the potential application of cannabinoids as antitumoral agents. Cannabinoid administration has been found to curb the growth of several types of tumor xenografts in rats and mice . Based on this preclinical evidence, a pilot clinical trial has been recently run to investigate the antitumoral action of THC on recurrent gliomas . Recent findings have also shown that the pro-apoptotic and tumor growth–inhibiting activity of cannabinoids relies on the upregulation of the transcriptional co-activator p8 and its target the pseudo-kinase tribbles homolog 3 (TRB3). ER stress–evoked upregulation of the p8/TRB3 pathway induced autophagy via inhibition of the Akt/mTORC1 axis and that activation of autophagy promoted the apoptotic death of tumor cells.

Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells,2009

Pharmacology

The pharmacological actions of THC result from its partial agonist activity at the cannabinoid receptor CB ₁ (K _i =10nM), located mainly in the central nervous system, and the CB ₂ receptor (K _i =24nM), mainly expressed in cells of the immune system. The psychoactive effects of THC are primarily mediated by its activation of CB ₁ G-protein coupled receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyclase.

The presence of these specialized cannabinoid receptors in the brain led researchers to the discovery of endocannabinoids, such asanandamide and 2-arachidonoyl glyceride (2-AG). THC targets receptors in a manner far less selective than endocannabinoid molecules released during retrograde signaling, as the drug has a relatively low cannabinoid receptor efficacy and affinity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor efficacy. THC is a lipophilic molecule and may bind non-specifically to a variety of receptors in the brain and body, such as adipose tissue (fat).

Several studies have suggested that THC also has an anticholinesterase action which may implicate it as a potential treatment for Alzheimer's and Myasthenia Gravis.

Metabolism

THC is metabolized mainly to 11-OH-THC by the body. This metabolite is still psychoactive and is further oxidized to 11-nor-9-carboxy-THC (THC-COOH). In humans and animals, more than 100 metabolites could be identified, but 11-OH-THC and THC-COOH are the dominating metabolites. Metabolism occurs mainly in the liver by cytochrome P450enzymes CYP2C9, CYP2C19, and CYP3A4. More than 55% of THC is excreted in the feces and about 20% in the urine. The main metabolite in urine is the ester of glucuronic acidand THC-COOH and free THC-COOH. In the feces, mainly 11-OH-THC was detected.

Wikipedia

ANTICANCER ACTION

Cancer is a disease characterized by uncontrolled division of cells and their ability to spread. This unregulated growth is caused by damage to DNA, resulting in mutations, defects in cell cycle, and apoptotic machinery. Thus, agents that can modulate apoptosis to maintain steady-state cell population by affecting one or more signaling intermediates leading to induction of apoptosis can be useful for targeted therapy of cancer.

Cannabinoids for Cancer Treatment: Progress and Promise, 2008

Cannabinoids induce autophagy of cancer cells and that this process mediates the cell death–promoting activity of these compounds. Several observations strongly support this idea: [a] THC induced autophagy and cell death in different types of cancer cells but not in nontransformed astrocytes, which are resistant to cannabinoid killing action, [b] pharmacological or genetic inhibition of autophagy prevented THC-induced cell death, [c ] autophagy-deficient tumors were resistant to THC growth-inhibiting action, and [d] THC administration activated the autophagic cell death pathway in 3 different models of tumor xenografts as well as in 2 human tumor samples.

RESULTS

Autophagy mediates THC-induced cancer cell death.
Double membrane vacuolar structures with the morphological features of autophagosomes were observed in THC-treated cells. The conversion of the soluble form of LC3 (LC3-I) to the lipidated and autophagosome-associated form (LC3-II) is considered one of the hallmarks of autophagy.

In addition, co-incubation with the lysosomal protease inhibitors E64d and pepstatin A, which blocks the last steps of autophagic degradation, enhanced THC-induced accumulation of LC3-II, confirming that cannabinoids induce dynamic autophagy in U87

THC induces autophagy via ER stress–dependent upregulation of p8 and TRB3.
In addition to the presence of autophagosomes, electron microscopy analysis of cannabinoid-treated cells revealed the presence of numerous cells with dilated ER.

Of interest, cannabinoid administration produced similar activation of ER stress and autophagy, as well as cell death, in other human astrocytoma cell lines and several human cancer cell lines of different origin, including pancreatic cancer, breast cancer, and hepatoma.

THC-induced accumulation of de novo–synthesized ceramide, an event that occurs in the ER, leads to upregulation of the stress-regulated protein p8 and its ER stress–related downstream targets, ATF4, CHOP, and TRB3, to induce cancer cell death.
THC-induced ER dilation, eIF2α phosphorylation, p8, ATF4, CHOP, and TRB3 upregulation and autophagy, supporting that ceramide accumulation is involved in cannabinoid-triggered ER stress and autophagy.

THC inhibits Akt and mTORC1 via TRB3.
Inhibition of mTORC1 is considered a key step in the early triggering of autophagy.
THC treatment of U87MG cells reduced the phosphorylation of p70S6 kinase (a well-established mTORC1 substrate) and the ribosomal protein S6 (a well-established p70S6 kinase substrate), indicating that mTORC1 is inhibited in cannabinoid-challenged cells. In addition, the cannabinoid-induced decrease in p70S6 kinase and S6 phosphorylation.
Activation of the autophagy-mediated cell death pathway is indispensable for cannabinoid antitumoral action.

Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells,2009

Schematic representation of signaling pathways associated with cannabinoid receptor activation induced by its agonists. Upon receptor binding, cannabinoid receptor agonists inhibit cell proliferation through inhibition of cAMP-dependent protein kinase, which activates mitogen-activated protein kinases (MAPK). Stimulation of ceramide synthesis via activation of serine pamitoyltranferase (SPT) up-regulates p8, leading to the subsequent induction of apoptosis. Cannabinoid receptor agonists also activates MAPKs and PI3K/Akt pathways; sustained activation of ERK1/2 leads to the induction of cyclin kinase inhibitor p27/KIP1with modulation of cell cycle regulatory molecules, resulting in G1arrest and apoptosis. The proposed mechanisms are based on the available literature and are cell specific, and not all pathways are triggered simultaneously. Further studies are needed to unravel the detailed mechanism of action of cannabinoid receptor activation by their agonists.CHOP, CAAT/enhancer binding protein homologous protein; PARP,poly(ADP)ribose polymerase; cdk, cyclin-dependent kinase. PKA, cAMP-dependent kinase.

Cannabinoids for Cancer Treatment: Progress and Promise, 2008

CONCLUSION

Overall, the cannabinoids may show future promise in the treatment of cancer, but there are many significant hurdles to be overcome. There is much still to be learned about the action of the cannabinoids and the endocannabinoid system. The current disagreements in the literature suggest gaps remain in the knowledge base around the normal signaling pathways used by endocannabinoids, the physiological systems that are involved, and the range of effects that these compounds cause. Future research will help clarify the actions of the cannabinoids, and particularly the endocannabinoid signaling pathway, which will be critical in the ongoing development of these compounds.

It is a distinct possibility that the cannabinoids may have a place in the future treatment of cancer. Several reports have shown that the synthetic cannabinoids in particular have the potential to show sufficient specificity and efficacy to be precursors to clinical treatments. However, at this point in time, the results from studies are lacking sufficient depth of understanding to allow this transition to occur. The contradictory nature of reports around the efficacy of compounds highlights our lack of detailed understanding of mechanisms of action. The resolution of the conflicting evidence around cannabinoid action will continue to be a research priority in the near future, and it is expected that developing a more robust understanding of the mechanisms of action underlying cannabinoid action will facilitate the acceptance of cannabinoid use in a clinical setting.

Critical appraisal of the potential use of cannabinoids in cancer management, 2013

Roma, 22 ott. 2012 - (Adnkronos Salute) - L'abuso di marijuana può provocare nausea ciclica, vomito ricorrente e dolori addominali. Sono gli effetti di un disturbo ancora poco conosciuta, la sindrome iperemetica da cannabinoidi. A rivelarlo è lo studio dello Scripps Green Hospital and Clinic di San Diego (Usa), presentato al 77esimo congresso dell'American College of Gastroenterology's di Las Vegas. Secondo i ricercatori l'effetto della sindrome, ancora poco studiato, ha un costo molto alto per il servizio sanitario "in quanto molto spesso per cercare di capire l'origine e le cause della nausea e del vomito i medici procedono con test diagnostici e trattamenti non proprio economici. Anzi molte volte inefficaci".
"I pazienti che fanno uso di cannabis, naturale o in forma sintetica chiamata 'Spice' - avvertono i ricercatori - non si rendono conto che gli episodi che manifestano con un certa ciclicità, come vomito e dolori addominali persistenti, possono essere il risultato della sindrome. Anzi - precisano - tendono ad aumentare il consumo della marijuana nel tentativo di alleviare proprio questi dolori. Ma - concludono - l'unica soluzione ai disturbi è quella di smettere con la cannabis".

Cannabis Sodium