These findings underline the importance of elucidating the full pharmacological effectiveness and the molecular mechanisms of the cannabinoid system in GBM pathophysiology.
The therapeutic effect of cannabinoids is based on reduction of tumor growth via inhibition of tumor proliferation and angiogenesis but also via induction of tumor cell death. Additionally, cannabinoids were shown to inhibit the invasiveness and the stem cell-like properties of GBM tumors.Recent phase II clinical trials indicated positive results regarding the survival of GBM patients upon cannabinoid treatment.
What is Glioblastoma?
Glioblastoma (GBM) is the most malignant brain tumor and one of the deadliest types of solid cancer overall. GBM is an extremely aggressive type of cancer. These tumors are characterized by high cellular proliferation and angiogenesis resulting in rapid tumor growth and, consequently, necrosis. GBM cells also exhibit high migration and invasive properties, which allow them to produce metachronous lesions and even to spread through the brain parenchyma. Furthermore, GBM tumors contain a subpopulation of glioma stem-like cells (GSCs), which, at least partially, account for the high resistance to therapy and recurrence rates of these tumors.
Molecular Mechanisms of Cannabinoids in GBM
GBM tumors are known to express both major cannabinoid-specific receptors CB1 and CB2. The expression of these receptors has been detected in GBM cell lines, in ex-vivo primary tumor cells derived from GBM patients and in situ, in GBM tissue biopsies. There is a general consensus that high-grade gliomas, including GBM, express high levels of CB2. Furthermore, CB2 expression positively correlates with the malignancy grade. In contrast, the expression of CB1 still requires characterization, as it has been reported to be either unchanged, decreased or even increased in GBM compared to low-grade gliomas or non-tumor control tissues.
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.
What Studies Says...???
A pilot clinical study was already developed more than a decade ago to investigate the anti-tumor activity of THC in patients with glioma. The study held promising results as it showed a decrease of tumor cell proliferation upon administration of THC in two of nine patients.
Other studies additionally showed that THC altered the balance between ceramides and dihydroceramides in autophagosomes and autolysosomes, which promoted the permeabilization of the organellar membrane, the release of cathepsins in the cytoplasm and the subsequent activation of apoptotic cell death.
Another stydie found that glioma cells treated with CBD responded with reactive oxygen species (ROS) production, GSH depletion and caspase-9, -8 and -3 activation. Furthermore, combined treatment of GBM cells with THC and CBD induced a significant increase in the formation of ROS, which was linked to a later induction of apoptosis.
Pre-clinical studies have also investigated the anti-tumor effects of cannabinoid combinations (in particular THC:CBD) and found that the anti-neoplastic effect of THC was enhanced when combined with CBD. The therapeutic potential of THC:CBD combinations was, tested in combination with standard GBM chemotherapy
In 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.
"Hopefully the study will spawn new understandings of how glioblastoma works and how cannabis can stop it."
Source: https://www.ncbi.nlm.nih.gov
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