Cancer research and cannabinoids

Cannabinoids: mechanisms in gliomas and its possible role in treatment

Virginia Thornley, M.D., Neurologist, Epileptologist

July 18, 2018

Glioblastoma multiforme is one of the most malignant types of cancer with a survival rate of less than 5% after 5 years. This may be due to a number of reasons including aggressive angiogenesis, active proliferation of cells and necrosis. In addition, it was found that there are a stem-cell like cells involved which may account for some of its resistance to treatment consisting largely of surgical resection and radiation treatments.

This looks into the role cannabinoids may play in the treatment of gliomas under which glioblastoma multiforme is categorized. Every mechanism is key in providing valuable information in targeting various mechanisms to assist with treatment.

Cannabinoid system and evidence of a role in gliomas

Phytocannabinoids have been identified from the plant cannabis sativa including delta-9-tetraydrocannabinol and cannabidiol. There are 2 significant receptors CB1 receptor and CB2 receptors. Within the endocannabinoid system there are 2 well-studied endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA) and G-related proteins (1). delta-9-tetrahydrocannabinol is a pharmacomimetic of anandamide while cannabidiol is a mimetic of 2-AG. Anandamide is metabolized by fatty acid amide hydrolase or FAAH while 2-AG is metabolized through monoacylglycerol lipase (MAGL).

The receptors are of 2 types. The CB1 receptor is found predominantly in the nervous system in areas subserving pain modulation, memory, and movement. The CB2 receptor is peripherally found in the immune system. The CB2 receptor is found to a lesser extent in other organ systems including adrenal, cardiac, endocrine, pulmonary, gastrointestinal and gynecological organs.  Cannabinoids react with the TRPV receptor or the transient receptor cation channel subfamily V. They can act on G receptors including GPR55 which is thought to influence inhibition of seizures. Other receptors include GPR12, GPR18, and GPR119 (2).

Evidence of a role in gliomas

In glioblastoma multiforme, degrading enzymes of anandamide were found to be reduced with 60% reduction of fatty acid amide hydrolase (FAAH). Anandamide was found to be significantly increased compared to non-tumor tissue. In meningiomas, 2-AG were found to be significantly increased. This points towards elevation of levels of endogenous cannabinoids in the presence of tumor cells which may possibly signal an anti-tumor process by modulating cannabinoid receptor mechanisms (3).

In pediatric low grade gliomas, it was found that in one cohort there was a spontaneous
involution of the tumors after a subtotal resection. Patients were followed 10 years. Analysis of gene expression and microRNA expression was studied. There was a different set of genes and microRNA expressions discovered in tumors that involuted spontaneously and those that were stable and showed no progression. The CB1 receptor was found to be expressed more abundantly using immunohistochemistry (4). This study suggests that CB1 receptor numbers may corroborate with a better prognosis and suggests a role of endocannabinoids in a more positive prognosis in pediatric low grade glioma.
How cannabinoids play a role in treatment against gliomas

There are various mechanisms by which cannabinoid can modulate the pathogenesis in tumors including proliferation, invasion, cell survival. Cannabinoids are thought to be involved mechanistically in the anti-proliferative, anti-migration and apoptotic effects of tumor cells in gliomas.

Cannabinoids may make tumor cells in gliomas more susceptible to radiation

One study found that cannabinoids may make tumor cells in gliomas more strongly susceptible to irradiation. When heat shock proteins were treated with CBD, they were upregulated. This did not occur in the setting of THC. Heat shock proteins are important in degradation, assembly,  and transcription  factor regulation. They are important in cell survival in the setting of abnormal pH, temperature and inflammation which may be caused by abnormal stability in the cell related to hypoxia, oxidative stress and temperature. Heat shock proteins are associated with resistance of tumor cells to treatment and a poorer prognosis (5). Heat shock proteins can inadvertently promote cancer cell survival, hence, their presence may correlate with a poorer prognosis. Cannabinoids were found to increase reactive oxidative stress leading to an alteration in the expression of HSP’s by increasing it. Increased HSP’s may alter the cytotoxicity of CBD towards cancer cells. By using an HSP inhibitor in conjunction with CBD, there may be better impact of irradiation of tumor cells. In summary, CBD along with HSP inhibitors may make tumor cells in gliomas more vulnerable to tumor irradiation (6).

Cannabinoids causes tumor cell death through apoptotic mechanisms

In one study, cannabinoids were found to have an anti-proliferative effect on tumors. Apoptosis is reduced by mechanisms where cannabinoids stimulate the pro-apoptotic ceramide which subsequently has impact on cell proliferation, differentiation and apoptosis in tumors (7).

In another study, there is supportive evidence that sphingolipid metabolism changes. This causes tetrahydrocannabinol to change the sphingolipid content in the endoplasmic reticulum, autolysosomes and autophagosomes. This contributes towards cell death promotion by autolysosomes which are stimulated by the cannabinoids (8).

Another study confirms that arachidonoylethanolamide (AEA) or anandamide which is the most potent endogenous cannabinoid works through anomalously expressed vanilloid receptor-1 (VR-1) in activating apoptosis in glioma cell lines through this receptor (9). THC is a mimetic of anandamide and may induce apoptosis through this mechanism. This may represent a potential specific molecular mechanism where therapeutic agents may be developed.


Cannabinoids reduce angiogenesis and proliferation of glioma cell lines

In the human cell glioma cell lines U-87MG and T98G, cannabidiol was found to inhibit the proliferation and cell invasion of these cancer cell lines. These results are significant since aggressive tumors have an ability for normal tissue invasion and proliferation leading to a poor outcome. The doses required for reduction of invasion was less compared to the dosage needed to prevent proliferation. Cannabidiol demonstrated the ability to inhibit different proteins necessary for cell invasion of the 2 cell lines including MMP-9, TIMP-1, TIMP-4, uPA, VEGF and SerpinE1-PAI. Their roles play a significant part in metastasis and vascular proliferation (10). Interestingly, T98G cell lines were found to be delta-9-THC resistant.

Cannabinoids reduce MMP9 which is important in tumor cell invasiveness

MMP are proteases and are increased in the presence of gliomas signaling the invasiveness of the tumor. Cannabinoid inhibition of MMP9 may be the way by which invasiveness of the tumor is reduced. Inhibition of TIMP was also noted in the presence of cannabinoids, which is demonstrated in clinically aggressive gliomas (10).

Cannabinoids inhibits HIF-1 which allows tumor cells to thrive in hypoxic settings

Another significant concept produced by the research is cannabidiol inhibition of HIF1-alpha (or hypoxia induced factor) which is a transcription factor serving a regulatory role in the setting of hypoxia. Hypoxia occurs in fast-growing tumors when the demands for oxygen are outpaced and hypoxia results. In the setting of hypoxia, HIF1-alpha allows tumor cells to thrive in hypoxic conditions through migration, survival and vascular proliferation allowing these tumors to be resistant to chemotherapy (10).

Cannabinoids can modulate mechanistic properties of tumor cells in gliomas

One study demonstrated that cell “stiffness” correlates with the aggressiveness of invasion from tumor cell lines and may represent a mechanistic cell marker to signal invasiveness of a tumor. Cannabinoids can modulate the mechanistic properties of tumors and may be a potential anti-tumor therapeutic target in glioma cell lines(11).


In summary, cannabinoids are proven to play a role in significant mechanisms involved in tumor activities including proliferation, migration, angiogenesis and survival. Cannabidiol is found to inhibit conditions where transcription factors cause cancer cells to thrive in hypoxic environments which is crucial in the aggressive profile of malignant tumors. Cannabidiol reduces MMP9 significant in invasiveness. Cannabidiol along with HIF inhibitors can make gliomas more radiation susceptible.

The pre-clinical studies are accumulating rapidly which each discovery. Every mechanism elucidated counts towards potential therapeutic targets in gliomas.



  1. Wang, et al. Quantitative Determination of delta 9-tetrahydrocannabinol, CBG, CBD, their acid precursors and five other neutral cannabinoids by UHPLC-UV-MS. Planta. Med, 2019, Mar., 84 (4):260-266
  2. Landa, et al, “Medical cannabis in the treatment of cancer pain and spastic conditions and options of drug delivery in clinical practice,”Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub., 2018, Mar; 162(1):18-25
  3. Petersen, G., Moesgaard, B., Schmid, P.C., Broholm, H., Kosteljanetz, M., Hansen, H.S. Endocannaboinoid metabolism in human glioblastomas and meningiomas compared to human non-tumour brain tissue. J. Neurochem. 2005, Apr., 93 (2):299-309
  4. Sredni, S.T., Huang, C.C., Suzuki, M., Chou, P., Tomita, T. Spontaneous involution of pediatric low-grade gliomas: high expression of cannabinoid receptor 1 (CNR1) at the time of diagnosis may indicate involvement of the endocannabinoid system. Childs Nerv. Sys.t 2016, Nov, 32(11):2061-2067
  5. Calderwood, S.K., Khaleque, A., Sawyer, D.B., Ciocca, D.R., Heat shock proteins in cancer: chaperones to tumorigenesis. Trends in Biochemical Sciences. 2006, Mar. 31(3):164-172 
  6. Scott, K.A., Dennis, J.L., Dalgeish, A.G., Liu, W.M. Inhibiting heat shock proteins can potentiate the cyototoxic effect of cannabidiol in human glioma cells. Anticancer Research. 2015, Nov., 35 (11):5827-583 
  7. Ellert-Miklaszewska, A., Ciechomska, I., Kaminska, B. Cannabinoid signaling in glioma cells. Adv. Exp. Med. Biol. 2013, 986:209-220
  8. Hernandez-Tiedra, s., Fabrias, G., Davila, D., Salanueva, I.J., Casas, J., Montes, L.R., Anton, Z., Garcia-Taboada, E., Salazar-Roa, M., Lorente, M., Nylandsted, J., Armstrong, J., Lopez-Valero, I., McKee, C.S., Serrano-Puebla, A., Garcia-Lopez, R., Gonzale-Martinez, J., Abad, J.L.,, Hanada, K., Boya, P., Goni, F., Guzman, M., Lovat, P., Jaatela, M., Alonso, A., Velasco, G. Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy, 2016, Nov. 12 (11):2213-2229
  9. Contassot, E., Wilmotte, R., Tenan, M., Belkouch, M.C., Schuriger, V., de Tribolet, N., Burkhardt, K., Dietrich, P.Y. Arachidonoylethanolamide induces apoptosis of human glioma cells through vanilloid receptor-1. J. Neuropathol. Exp. Neurol. 2004 Sep, 63(9):956-63
  10. Solinas, M., Massi, P., Cinquina, V., Valenti, M., Bolognini, D., Gariboldi, M., Monti, E., Rubino, T., Parolaro, D. Cannabidiol, a non-psychoactive cannabinoid compound, inhibits proliferation and invasion in U87-MG and T98G glioma cells through multitarget effect. PLoS One 2013, 8(10):e76918
  11. Hohmann, T., Grabiec, U., Ghadban, C., Feese, K., Dehghani, F. The influence of biomechanical properties and cannabinoids on tumor invasion. Cell Adh Migr 2017, 11(1):54-67


Cancer research and cannabinoids

Cannabinoids: a review on pre-clinical studies on anti-angiogenesis, apoptosis and reduction of MMP-2 expression inhibiting cancer cell growth

Virginia Thornley, M.D., Neurologist, Epileptologist

June 24, 2018



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.


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