Antitumorigenic Effects of Cannabinoids beyond Apoptosis

“According to the World Health Organization, the cases of death caused by cancer will have been doubled until the year 2030. By 2010, cancer is expected to be the number one cause of death. Therefore, it is necessary to explore novel approaches for the treatment of cancer. Over past years, the antitumorigenic effects of cannabinoids have emerged as an exciting field in cancer research. Apart from their proapoptotic and antiproliferative action, recent research has shown that cannabinoids may likewise affect tumor cell angiogenesis, migration, invasion, adhesion, and metastasization. This review will summarize the data concerning the influence of cannabinoids on these locomotive processes beyond modulation of cancer cell apoptosis and proliferation. The findings discussed here provide a new perspective on the antitumorigenic potential of cannabinoids.

Conclusion

Recent investigations have shown that besides its well known antiapoptotic and antiproliferative action, cannabinoids may also confer antiangiogenic, antimigrative, antiadhesive, anti-invasive, and antimetastatic properties by pathways including activation of both cannabinoid receptors as well as TRPV1. Although a limited number of studies have been published addressing the underlying mechanisms, the currently available results indicate that the modulation of several components of signal transduction pathways, including Src, nuclear factor κB, ERK1/2, HIF-1α, Akt, and modulation of the expression as well as that of the enzymatic action of proteins of the MMP family, EGF, VEGF, IgSF CAMs, and FAK, by cannabinoids might support beneficial effects on tumor cell locomotion and spreading. Based on these facts, evidence is emerging to suggest that cannabinoids are potent inhibitors of both cancer growth and spreading. Because cannabinoids are usually well tolerated and do not develop the toxic effects of conventional chemotherapeutics, more preclinical studies are warranted to investigate a potential utility of these substances as anticancer therapeutics.”

http://jpet.aspetjournals.org/content/332/2/336.long

Towards the use of cannabinoids as antitumour agents.

“Various reports have shown that cannabinoids (the active components of marijuana and their derivatives) can reduce tumour growth and progression in animal models of cancer, in addition to their well-known palliative effects on some cancer-associated symptoms. This Opinion article discusses our current understanding of cannabinoids as antitumour agents, focusing on recent insights into the molecular mechanisms of action, including emerging resistance mechanisms and opportunities for combination therapy approaches. Such knowledge is required for the optimization of preclinical cannabinoid-based therapies and for the preliminary clinical testing that is currently underway.”

http://www.ncbi.nlm.nih.gov/pubmed/22555283

Endocannabinoids in endocrine and related tumours.

“The ‘endocannabinoid system’, comprising the cannabinoid CB1 and CB2 receptors, their endogenous ligands, endocannabinoids and the enzymes that regulate their biosynthesis and degradation, has drawn a great deal of scientist attention during the last two decades. The endocannabinoid system is involved in a broad range of functions and in a growing number of physiopathological conditions. Indeed, recent evidence indicates that endocannabinoids influence the intracellular events controlling the proliferation of numerous types of endocrine and related cancer cells, thereby leading to both in vitro and in vivo antitumour effects. In particular, they are able to inhibit cell growth, invasion and metastasis of thyroid, breast and prostate tumours. The chief events of endocannabinoids in cancer cell proliferation are reported highlighting the correspondent signalling involved in tumour processes: regulation of adenylyl cyclase, cyclic AMP-protein kinase-A pathway and MEK-extracellular signal-regulated kinase signalling cascade.

Up to date since the isolation and characterisation of the psychoactive component of Cannabis sativa, Δ9-tetrahydrocannabinol (Δ9-THC), about 60 different plant terpeno-phenols more or less related to THC have been isolated and defined cannabinoids. They include cannabidiol (CBD), cannabinol, cannabigerol and cannabichromene. The discovery of these principles stimulated the generation of a whole range of synthetic analogues that included not only compounds structurally similar to phytocannabinoids, but also analogues with different chemical structures, including classic and non-classic cannabinoids and aminoalkylindoles (Howlett et al. 2002) as well as the subsequently discovered endogenous arachidonic acid derivatives or endocannabinoids. The discovery of this family of endogenous cannabinoids (Devane et al. 1992, Mechoulam et al. 1995, Sugiura et al. 1995) has focused much attention on cannabinoids and their pharmacological properties during the last few years (Di Marzo et al. 2004).”

http://erc.endocrinology-journals.org/content/15/2/391.long

Cannabinoid receptor activation correlates with the pro-apoptotic action of the β2-adrenergic agonist, (R,R’)-4-methoxy-1-naphthylfenoterol, in HepG2 hepatocarcinoma cells

“In the last several years, development of new CBR ligands has become an intense area in cancer research because of the role of the endocannabinoid system in the regulation of cell proliferation and apoptosis…

The therapeutic potential for synthetic small bivalent ligands holds great promise as new lead compounds in a wide range of disparate diseases.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464034/

Anti-tumoral Action of Cannabinoids

“Delta9-Tetrahydrocannabinol, the main active component of marijuana… Here, we show that intratumoral administration of Delta9-tetrahydrocannabinol… induced a considerable regression of malignant gliomas… Cannabinoid treatment did not produce any substantial neurotoxic effect… cannabinoids signal apoptosis (cell death/suicide) by a pathway involving cannabinoid receptors… These results may provide the basis for a new therapeutic approach for the treatment of malignant gliomas.”

‎”Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death…”

http://www.ncbi.nlm.nih.gov/pubmed/10700234

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

“Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide… few therapeutic options are available… we investigated the effects of cannabinoids–a novel family of potential anticancer agents–on the growth of HCC. We found that Δ(9)-tetrahydrocannabinol (Δ(9)-THC, the main active component of Cannabis sativa)… reduced the viability of the human HCC cell lines…cannabinoids were also able to inhibit tumor growth… Our findings may contribute to the design of new therapeutic strategies for the management of HCC.”

http://www.ncbi.nlm.nih.gov/pubmed/21475304