Virginia Thornley, M.D., Neurologist, Epileptologist
June 24, 2018
@VThornleyMD
Introduction
The surge of recognition of the medical significance of the cannabis sativa can no longer be ignored. Frustrated with the futility of current pharmaceutic agents, their associated side effects and costs, there is a growing tendency for more natriceutic measures of therapy. Shunned by physicians and by the public, there is a growing clamoring of medical marijuana advocates for its use. There is only a small proportion of physicians qualified to recommend this agent. Prescribing is federally illegal as it is still classified as category I drug. In the state of Florida alone, as of June 2018, out of 75,000 licensed physicians, only 2100 are qualified to recommend it or 2%. Long known for the stigma of its recreational value, its foothold in the medical community is slow-going. Most of the public associates the plant with unseemly, clandestine purposes. The federal law against it stands steadfast, with legislation moving at a molasses pace, even while recognized by state laws. These variables account for the great difficulty procuring this agent which is not only organic and all natural but medical in nature.
However, there is great interest in this plant. The pre-clinical data shows promise but more larger clinical trials are still needed. It seems to be far reaching in its effects and because it is still not well-studied, the vast number of purposes is still largely unknown.
Interest turns towards any anti-neoplastic application it might have. Pre-clinical data has shown some promise, although it may not always translate into human results. The scientific data points towards some benefits in the neoplastic process.
Endocannabinoid system
In an overview of the endocannabinoid system, there are 2 cannabinoid receptors, CB1 and CB2. The CB1 receptor is abundant in the nervous system and found to a lesser extent in other systems. It is through this receptor that psychoactive properties are activated. The CB2 receptor is found largely in the immune system. Anandamide interacts with the CB1 receptor, of which delta-9-tetrahydrocannabnol is a pharmacomimetic. While 2-AG or di-arachidonoylglycerol is a low affinity agonist at the CB1 receptor. Cannabidiol (CBD)is a mimetic of 2-AG, where 100 times the amount of CBD is needed to get the same effect as THC. It has a full ligand effect on the CB2 receptor. The CB1 receptor is a G-protein coupled receptor. Cannabidiol interacts with the TPRV transient receptor potential channel and the GPR or G-protein receptor family. Expression of the cannabinoid receptors are most notable in areas engaged with memory, motor, learning, emotions and endocrine functions.
Endocannabinoids and the role in cancer
The beneficial effects of cannabinoids on symptoms pertaining to neoplasms such as anorexia, nausea and pain are well-known. Investigations turn towards any effect on the actual neoplastic process.
An upregulation of CB receptors are found in high volume in cancerous processes. The enzymes involved are also at high levels. This suggests that the endocannabinoid system may play a role in the neoplastic process. The frequency of the receptors and amount of enzymes may correlate with the aggressiveness of the type of cancer. This suggests that the endocannabinoid system may be revved up and play a role in promoting a pro-tumor environment.
Conversely, there are studies suggesting that activation of the cannabinoid system may be anti-tumorigenic. Reduction of tumor growth was observed with a reduction in the endocannabinoid degrading enzymes(1).
While there are some inconsistencies, overall, the anti-tumorigenic effects appear to be better demonstrated in pre-clinical studies.
Effect on tumor cells
Overall, there are more studies that cannabinoids including phytocannabinoids such as tetrahydrocannabinol and cannabidiol and synthetic cannabinoids such as JWH-017 show anti-tumorigenic effects.
In one study, the CB1 receptors were found to inhibit the anti-metastatic nature of the K562 cell line which acts as a chronic myelogenous leukemia model in the study (2).
In glioblastoma multiforme tumors, CB1 and CB2 receptors are both expressed. Altered expressions of the receptors were thought to correlate with the manifestation of gliomas and glioblastoma multiforme. Cannabinoids are thought to manifest anti-proliferative activity against tumor cells by 2 mechanisms: anti-neogenesis of vasculature and promotion of apoptosis (3). In one study of glioma stem cell-like cells from glioma cell lines and glioblastoma multiforme biopsies, there was demonstration of the presence of CB1 and CB2 receptors. CB receptor activation changed the gene expression that controlled the stem cell multiplication and differentiation. in addition, cannabinoids were found to reduce cells with the biomarker nestin which is a neuroepithelial cell progenitor. Cannabinoid treated stem like cells resulted in more differentiation and reduced expression of nestin which promotes glioma formation (3).
Cannabinoids were found to reduce angiogenesis by inhibiting the migration of vascular endothelial cells and by stopping the expression of MMP and proangiogenic factor in neoplastic cells (4). By preventing the increased vasculature cell migration, tumor growth is suppressed. With cannabinoids selectively acting on tumor cells, apoptosis is rendered resulting further in the blocking the growth of cancer cells resulting in the reduction in the proliferation of cancer cells (4). This study is significant because cannabinoids might be developed to achieve effect on reducing proliferation of tumor cells.
In a significant mouse model study, cannabinoids were found to reduce the activity of metalloproteinase matrix in glioma like cells. C6.9 and C6.4 glioma cell lines were used which are cannabinoid models showing cannabinoid responsive and resistant responses. Biopsy samples of 2 patients with multiforme glioblastoma were used. The cells were treated with tetrahydrocannabinol, JWH-133 a synthetic cannabinoid with CB2 receptor agonist effects and fumonisin. MMP was measured. The C6.9 cell line was found to have less tumor cell growth and less MMP-2 expression found on western blot using SDS-PAGE when treated with cannabinoids. It selectively reduced MMP-2, other MMP’s remained the same level. In C6.4 cell lines, tumor growth and level of MMP-2 were not affected. The study demonstrates that cannabinoids inhibit tumor cell growth and lowers MMP-2. MMP-2 is expressed in many different cancer lines especially aggressive activity. While the tumor generation is more complex than this, the study adds significant information about tumor genesis and a role of cannabinoids in suppressing cancer growth (5).
In summary
Cannabinoids can affect the aggressiveness of tumors by inhibiting the vascular neogenesis. In addition in the animal model for gliomas, it is demonstrated to suppress cancer cell growth and the expression of MMP-2 which is associated with many neoplastic cell lines. More studies are needed as the neoplastic process is complex. In addition, pre-clinical studies need to be translated into human studies. Every mechanism elucidated helps towards understand the complex pathophysiology of cancer and potential therapeutic targets.
References
1.Śledziński, P., Zeyland, J., Słomski, R., Nowak., A. The current state and future perspectives of cannabinoids in cancer biology. Cancer Biology. 2018; 7(30):765-775
2, Gholizadeh, F., Gharehmani, M.H., Aliebrahimi, S., Shadboorestan, A., Ostad, S.N. Assessment of cannabinoids agonist and antagonist in invasion potential of K562 cancer cells. Iran Biomed. 2018 (epub ahead of print)
3. McAllister SD, Soroceanu L, Desprez P-Y. The antitumor activity of plant-derived non-psychoactive cannabinoids. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. 2015;10(2):255-267. doi:10.1007/s11481-015-9608-y.
4. Blazquez, C., Casanova, M.L., Planas, A., del Pulgar, T.G., Villanueva, C., Fernandez-Acenero, M.J., Aragones, J., Huffman, J.W., Jorcano, J.L., Guzman, M. Inhibition of tumor angiogenesis by cannabinoids. FASEB J. 2003, Jan., 17(3):529-531
5. Blazquez, C., Salazar, M., Carracedo, A., Lorente, M., Egia, A., Gonzalez-Feria, L., Haro, A., Velasco, G., Guzman, M. Cannabinoids inihibit glioma cell invasion by down regulating matrix metalloproteinase-2 expression. Neuropharmacology. 2008, Jan. 54(1):235-243
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