How marijuana was used to shrink one of the most aggressive brain cancers
Widely proscribed around the world for its recreational uses, cannabis is being used in a number of different therapeutic ways to bring relief for severe medical conditions. Products using cannabinoids, the active components of the cannabis plant, have been licensed for medical use. Sativex, for example, which contains an equal mixture of the cannabinoids tetrahydrocannabinol (THC) and cannabidiol (CBD), is already licenced as a mouth spray for multiple sclerosis and in the US, dronabinol and nabilone are commercially available for treating cancer-related side effects.
Now, in a study published in Molecular Cancer Therapeutics, we’ve also shown that cannabinoids could play a role in treating one of the most aggressive cancers in adults.
There are more than 85 cannabinoids, which are known to bind to unique receptors in cells and which receive outside chemical signals. These receptors feed into signalling pathways, telling cells what to do. Recent studies have shown that some cannabinoids have potent anti-cancer action. For example, both THC and CBD have been shown in a number of laboratory studies to effectively induce cell death in tumour cells by modifying the faulty signalling pathways inside these cells. Depending on the cell type this can disrupt tumour growth or start to kill it.
The psychoactivity associated with some cannabinoids, principally THC (which gives people a cannabis high), is also mediated via the same receptors. Because these receptors are found in the highest abundances in brain cells, it follows that brain tumours also rich in these receptors may respond best to cannabinoids.
We wanted to investigate the anti-cancer effects of Sativex in glioma cells. High-grade glioma is an aggressive cancer, with very low long-term survival rates. Statistics show that just over a third (36%) of adult patients in the UK with glioma live for at least a year, while the five-year survival rate is 10%.
Depending on the individual, treatment can consist of surgery, radiotherapy, and/or chemotherapy with the drug temozolomide. However, due primarily to the intricate localisation of the tumour in the brain and its invasive behaviour, these treatments remain largely unsuccessful.
However, as our study showed, combining radiotherapy with cannabinoid treatment had a big effect.
Finding the right dose
We first had to perform lab tests on cells to optimise the doses of the cannabinoids, and showed that CBD and THC combined favourably.
We found that to achieve a 50% kill rate of glioma cells, a dose of 14mM (millimolar – a measure of amount-of-substance concentration) of CBD or 19mM of THC would be needed if each was used singularly. However, when used in combination, the concentrations required to achieve the same magnitude of cell kill is significantly reduced to just 7mM for each. This apparent reduction in the doses of the cannabinoids, in particular THC, without a loss of overall anti-cancer action is particularly attractive as unwanted side effects are also reduced.
Once we had these results, we then tested the impact of combining the cannabinoids with irradiation in mice with glioma. The efficacy of this treatment was tracked using sophisticated MRI technology – and we determined the effects on tumour growth of either CBD and THC together, irradiation, or the combination of both. The drugs were used at suboptimal doses to allow us to see if there was any improvement in the therapy from combining them.
Balancing anti-cancer with psychoactive
In principle, patients treated with THC could experience some psychoactive activity. But the secret to successfully exploiting cannabinoids as a treatment for cancer is to balance the desired anti-cancer effects with the less desirable psychoactive effects. This is possible, as some cannabinoids seem to function independently of the receptors and so do not engage the adverse effects. CBD is one such cannabinoid. The doses of THC we selected were below the psychoactive level, but together with CBD it partnered well to give the best overall anti-cancer effect.
Our results showed that the dose of irradiation we used had no dramatic effect on tumour growth, whereas CBD and THC administered together marginally reduced tumour progression. However, combining the cannabinoids with irradiation further impeded the rate at which tumour growth progressed and was virtually stagnant throughout the course of the treatment. Correspondingly, tumour sizes on the final day of the study were significantly smaller in these subjects compared with any of the others.
The results are promising. There may be other applications but for now it could provide a way of breaking through glioma and saving more lives.
By Wai Liu, St George’s, University of London
Wai Liu receives funding from GW Pharmaceuticals.