CBD, or cannabidiol, is the second most common active ingredient in marijuana. CBD is obtained directly from the Cannabis sativa L. hemp plant. Cannabinoids are over 80 chemicals found in the Sativa plant. Cannabis sativa L. is a distinctively versatile plant and an important herbaceous species native to Central Asia that has long been used in traditional medicine and as a source of textile fabric.
The extraction of two active chemicals, CBD (cannabidiol) and THC (Delta 9 tetrahydrocannabinol) are for therapeutic purposes from the hemp plant Cannabis sativa L. Delta-9-tetrahydrocannabinol also known as THC is the most well-known component of cannabis. CBD (cannabidiol), on the other hand, is a non-intoxicating chemical component derived from hemp, a strain of the Cannabis sativa plant with only trace amounts of THC. Clinical trials show that CBD helps with conditions such as chemotherapy-induced nausea and anorexia and also helps in the symptomatic relief of multiple sclerosis. CBD appears to have effects on some brain chemicals, but they are not the same as THC’s effects.
Gliomas are the most common primary central nervous system tumours. Glioblastomas (GBMs), which are extremely aggressive types of cancer, account for half of the newly diagnosed gliomas. The vast majority of GBM patients develop primary GBM; however, secondary GBM can develop from lower-grade gliomas. Primary GBM is more common in men, whereas secondary GBM is more common in women. These tumours have high cellular proliferation and angiogenesis (a physiological process in which new blood vessels form from pre-existing blood vessels. When tumour cells require nutrients and oxygen, this stimulates this process), resulting in rapid tumour growth and death of tissue or cells. GBM cells are also highly migratory and aggressive, allowing them to form metachronous lesions and spread throughout the brain parenchyma resulting in brain tumours.
The current standard of care for GBM treatment is maximum safe surgical resection followed by radiotherapy with concurrent and adjuvant chemotherapy with temozolomide. GBM patients have a poor prognosis despite this aggressive treatment regimen. Advances in molecular pathology have identified various GBM subtypes, paving the way for more personalized therapeutic approaches. GBM, on the other hand, is still incurable, and there is an urgent need to target the molecular mechanisms involved in its progression.
Cannabinoids’ Molecular Mechanisms in GBM
Several studies show the alteration of cannabinoid receptors in gliomas and GBM. This discovery sparked the idea of the use of cannabinoid receptor agonists in treating cancer. Indeed in 2006 Guzman conducted a feasible clinical study to investigate THC’s anti-tumour activity in patients with glioma. The study yielded promising results, as THC administration reduced tumour cell proliferation in two of nine patients. Since then, a growing number of studies have attempted to elaborate on the molecular mechanisms of cannabinoids.
Cannabinoids and the Growth of GBM Tumors
The most well-studied effect of cannabinoids on GBM pathophysiology is tumour growth inhibition. Several in vivo studies have shown that cannabinoids can significantly reduce tumour volume in orthotopic and subcutaneous glioma animal models. The mechanisms that mediate this phenomenon can be divided into three categories:
1. Mechanisms that cause cell death (apoptosis and cytotoxic autophagy)
2. Mechanisms that inhibit cell proliferation
3. Anti-angiogenic mechanisms
Cannabinoids and the Invasion of GBM
Although gliomas and GBM rarely spread rapidly, these tumour cells can skillfully infiltrate the surrounding healthy brain tissue and spread through the brain parenchyma. As a result, therapeutic strategies aimed at inhibiting GBM cell migration and invasion have high clinical relevance in the treatment of this disease. The role of cannabinoids in GBM migration and invasion is still unknown. Nonetheless, evidence suggests that cannabinoids have potent anti-invasive effects on glioma cells in vitro and in vivo.
Soroceanu, for example, demonstrated in 2013 that CBD inhibited the invasion of GBM cells via organotypic brain slices. CBD inhibited protein-coding gene expression, which was attributed to its anti-invasive effect in several GBM cell lines, ex-vivo primary GBM cells, and an orthotopic xenograft murine model. Solinas discovered that CBD inhibited GBM invasion even at low concentrations that were insufficient to induce tumour cell death. The authors also demonstrated that CBD treatment of GBM cells significantly reduced the expression of major proteins involved in tumour invasion.
Future Perspectives of cannabinoids in GBM Therapies
According to decades of research from all around the world, cannabinoids show promising anti-neoplastic functions in GBM, according to decades of research, by targeting multiple cancer hallmarks such as resistance to programmed cell death, neoangiogenesis, tissue invasion, or stem cell-induced replicative immortality. Cannabinoids’ effects might become enhanced if combined with other cannabinoids or with chemotherapeutic agents. This, however, necessitates a thorough understanding of cannabinoid-induced molecular mechanisms and pharmacological effects. Finally, the findings of various preclinical and clinical studies may aid in the development of improved therapeutic strategies against GBM and, possibly, other nervous system diseases.