Glioblastoma (GBM) is the most malignant brain tumor and one of the deadliest types of solid cancer overall. More than 95% of GBM patients die within 5 years after diagnosis. Accumulating evidence indicates that cannabinoids have potent anti-tumor functions.
Glioblastoma...
Half of newly-diagnosed gliomas are glioblastomas (GBMs), with an incidence in adults of 0.59 3.69 cases per 100,000 person life-years. Primary GBM occur more commonly in male patients whereas the reverse is the case for secondary GBM. The mean age of primary and secondary G BM patients is 62 and 45 years, respectively (Adamson et al., 2009).
Cannabinoids...
The term cannabinoids originally described bioactive constituents of the plant Cannabis sativa. The cannabis ingredients were used traditionally for their medicinal purpose but also for their recreational properties. Most of the cannabinoids bind to G-protein coupled cannabinoid receptors, CB1 and CB2, and act as agonists or inverse agonists.
Activation of G-alpha i/o-coupled cannabinoid receptors inhibits adenylate cyclases, signals via ceramide, and induces kinase phosphorylation. Cannabinoid receptors also regulate the expression of immediate early genes and regulate the production of nitric oxide.
Molecular Mechanisms of Cannabinoids in GBM...
GBM tumors are known to express both major cannabinoid-specific receptors CB1 and CB2. CB2 expression positively correlates with the malignancy grade. In contrast, the expression of CB1 still requires characterization. The identification of altered expression of cannabinoid receptors in gliomas and GBM led to the hypothesis that cannabinoid receptor agonists might be used as anticancer agents.
Cannabinoids and GBM Tumor Growth...
Cannabinoid-induced cell death occurs mainly through the intrinsic (mitochondria-dependent) apoptotic pathway. The activation of the intrinsic apoptosis pathway by cannabinoids is thought to be mediated by an increase in intracellular ceramide. THC altered the balance between ceramides and dihydroceramides in autophagosomes and autolysosomes, which promoted the permeabilization of the organellar membrane.
In addition to ceramide-mediated cell death, cannabinoids were also shown to trigger apoptosis via oxidative stress. CBD treatment of glioma cells did induce a significant increase in ROS production. This phenomenon was accompanied by an upregulation of a large number of genes belonging to the heat-shock protein (HSP) super-family. It is proposed that the inclusion of HSP inhibitors might enhance the anti-tumor effects of cannabinoids.
The inhibitory effects of cannabinoids on GBM growth are not restricted to the direct modulation of tumor cell death/survival or proliferation pathways. Several studies showed that cannabinoids were also able to inhibit tumor angiogenesis. Local administration of THC resulted in a decrease of pro-angiogenic VEGF levels in two patients with recurrent GBM (Blazquez et al., 2004) In vitro, cannabinoids inhibited endothelial cell migration via the ERK pathway.
Recent evidence suggests that CB1 antagonists might also be useful in glioma therapy. Ciaglia et al. (2015) found that the pharmacological inactivation of CB1 by SR141716 inhibitedglioma cell growth through cell cycle arrest.
Cannabinoids and GBM Invasion...
The role of cannabinoids in GBM migration and invasion is still poorly characterized. accumulating evidence suggests that cannabinoids have potent anti-invasive effects on glioma cells both in vitro and in vivo. Although gliomas and GBM rarely metastasize, these tumor cells are very adept at infiltrating the surrounding healthy brain tissue and spreading through the brain parenchyma.
Cannabinoids and Glioma Stem-Like Cells (GSCs)...
A major challenge for GBM treatment is the resistance of the recurrent tumor to therapy. Evidence indicates that a subpopulation of GSCs contributes to this phenomenon through multiple mechanisms. Cannabinoid agonists altered the expression of genes involved in stem cell proliferation and differentiation.
CBD was shown to inhibit the self-renewal of GSCs via activation of the p38-MAPK pathway and downregulation of key stem cell mediators. Co-treatment with antioxidants abrogated these effects.
Clinical Relevance and Future Perspective of Cannabinoids in GBM Therapy...
The antineoplastic effects of cannabinoids have been investigated in a number of in vitro and in vivo studies. A pilot phase I clinical trial for the treatment of GBM patients indicated a good safety profile for THC. A tumor-specific cytostatic/cytotoxic effect of cannabinoids would, therefore, have great relevance for the Treatment Of GBM. In a GBM xenograft model in nude mice, the reduction of tumor size could be enhanced by co-administration of THC with CBD.
Conclusion...
Cannabinoids show promising anti-neoplastic functions in GBM by targeting multiple cancer hallmarks such as resistance to programmed cell death, neoangiogenesis, tissue invasion or stem cell-induced replicative immortality. The effects of cannabinoids can be potentially enhanced by combination of different cannabinoids with each other or with chemotherapeutic agents.
This requires, however, a detailed understanding of cannabinoid-induced molecular mechanisms and pharmacological effects. Ultimately, these findings might foster the development of improved therapeutic strategies against GBM and, perhaps, other diseases of the nervous system as well.
Sourse: https://www.ncbi.nlm.nih.gov
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