Cancer research and cannabinoids

Cannabinoids: mechanisms in gliomas and its possible role in treatment

Virginia Thornley, M.D., Neurologist, Epileptologist
@VThornleyMD

July 18, 2018

Introduction
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).

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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.

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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).

Summary

In summary, cannabinoids are demonstrated to have a role in significant mechanisms involved in tumor activities including anti-proliferation, anti-migration, anti-angiogenesis and anti-survival. Cannabidiol 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. Pre-clinical studies do not always translate to human studies but the science is gaining headway.

Introduction/Disclaimer

About

References
  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

 

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