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Glioblastoma and cannabis: Mechanisms of beneficial and adverse effects

Cannabinoids have generally accepted palliative effects on some symptoms related to cancer of all types; accumulating preclinical data suggest that cannabinoids may reduce tumor growth in animal cancer models. This is achieved by influencing the signaling of specific biochemical pathways, which are involved in controlling the proliferation of cancer cells as well as their survival. Besides, cannabinoids seem to inhibit neo-angiogenesis and reduce the invasiveness of tumors (in animal studies). Human studies of this sort are not available yet. We will here address specifically glioblastoma multiform (GBM), one of the deadliest and most treatment-resistant cancers in humans.

Ceramide- and ROS-related effects of cannabinoids on glioblastoma multiforme (GBM)
Ceramide- and ROS-related effects of cannabinoids on glioblastoma multiforme (GBM)
Basic cannabis-dependent pathways in GBM. Credit: Dumitru et al, 2018, Front Mol Neurosci 11:159

The first step of these cannabis-induced beneficial mechanisms in GBM is the increase of intracellular production of a lipid molecule, named ceramide, by a mechanism dependent on the CB1 receptor. Prolonged ceramide accumulation within the cytoplasm may cause the following:

• Cancer cell apoptosis with two different mechanisms. These are the regulation of (i) the ERK pathway (Extracelular signal-Regulated Kinase) and (ii) the AKT pathway (proteokinase B).

• Inhibition of the cell life cycle (that leads to proliferation) through the inhibition of cyclin A, but also the activation of factor p16, which is a tumor suppressor (the drug Flavopiridol/Alvocidib acts with a similar mechanism; in contrast to cannabinoids, it is accompanied by adverse effects).

• Inhibition of neo-angiogenesis by inhibition of VEGF factor, which signals the production of neo-vessels in the anoxic core of the tumor (Bevavacizumab / Avastin acts with a similar mechanism; unlike cannabinoids, it is oftentimes accompanied by serious side effects).

• Inhibition of local tissue invasion, achieved through the production of stress factor p8, which inhibits the production of metalloproteinases (MMPs), which are essential for local tissue degradation. Pharmaceutical inhibitors of MMPs are not currently available for clinical application.

Cannabinoids, especially CBD, also induce the production of free radicals (ROS) within GBM cells. This action is similar to that of the basic chemotherapeutic agent for GBM, temozolomide (TMZ), which is why these two substances work better together than each one alone. ROS production:

• Prevents the renewal of the tumor by its stem-like cells; this is extremely important because this prevents recurrences. This action is mediated by the activation of the p38/MAPK system.

• Promotes apoptosis of cancer cells, by inducing oxidative stress through depletion of the basic intracellular antioxidant, glutathione.

But one should not be overly enthusiastic: Cannabinoids have not only beneficial effects but adverse ones as well: they may promote the survival of cancer cells through stimulation of tumor-protective autophagy. This mechanism, which is partly dependent on cannabis, is central to the rescue of GBM cells (a similar problem arises with TMZ).

• Through ceramide accumulation: The basic biochemical growth pathway mTORC1 is suppressed, and cancer cells are forced to turn into survival mode, ie to enter a state of autophagy.

• By stimulating the vanilloid receptor TRPV2, which also signals autophagy in GBM stem cells, thus favoring relapse of the tumor.

The mechanism of autophagy, by which cancer cells survive mainly from nutritional stress, may not necessarily harm the patient’s survival, because it is limited in time. The limits depend on the availability of resources, that is energy and building materials (eg ATP, glycogen, protein, fat) and cannot last too long. It is at this point that proper nutrition and other epigenetic therapeutic factors that may already have caused generalized autophagy in the body, will not allow CBD-induced autophagy to last for so long.

The delicate balance between apoptosis and tumor-protective autophagy is what determines the therapeutic outcome; it is understandable that if one would add other treatment modalities that promote apoptosis (oncothermia and radiotherapy are both classic and proven), properly combined over time, greatly increases the chances of a successful outcome, and in fact with a good quality of life.

Apoptosis vs. Autophagy in GBM: A delicate balance
Apoptosis vs. Autophagy in GBM: A delicate balance
Apoptosis vs. Autophagy: Which one will prevail in our GBM patient? Credit: Modified from Trejo-Solis et al, 2018, Int J Mol Sci, 19: 3773

Also, the proper management of cannabinoids during treatment, so that the mechanisms of autophagy may not prevail, is of great importance, as is the utilization of CBG, which from early studies seems to deserve a better place in the treatment of GBM, especially in cases with THC intolerance. New preliminary data show that the non-psychoactive combination of CBG and CBD in vivo (without THC or TMZ) can double the cytotoxic effect of CBD on GBM cells. The inhibition of cell viability by CBD is complemented by CBG-induced apoptotic effect on GBM stem cells (GSCs), and regular tumor cells as well. GSCs are very slow-reproducing cells residing mostly at hypoxic niches within the tumor, and thus extremely resistant to chemo- and radiotherapy. At this point is where combining oncothermia + CBG to TMZ + THC + CBD can prevent a sizable number of recurrences, since oncothermia is the most important radiosensitizer of solid tumors. The particular contribution of CBG is, reportedly, to induce apoptosis to roughly 1/3 of GSCs, but only at high concentrations (about 50μΜ).

Given all the above, one can easily explain the diverse outcomes that our GBM patients get with their treatments: There are simply too many parameters to take into account and too many subtleties that influence the balance between cancer-cell death (apoptosis) and cancer-cell rescue (autophagy). And, of course, there are genetic differences among tumors: Not all GBMs will equally respond to the same treatment, and, unfortunately, there can be no accurate prediction of outcomes. We, integrative physicians, are doing our best; this is all we can promise for the time being. But things are advancing, so let’s have hope.

In conclusion, cannabis offers more benefits than adverse effects in patients with GBM. If used early in the course of the disease, with knowledge of the intricate subtleties of the matter, and especially in combination with other therapeutic modalities (temozolomide, oncothermia, epigenetics, etc.) in an integrative therapeutic frame, cannabis may significantly improve the outcome in cases of GBM. Clinical trials are underway.

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