Glial cells express cannabinoid receptors related to cell viability (Stella, 2010).

The specific cannabinoid receptors CB2 and GPR55 are overexpressed in glioblastomas compared to non-cancer glial cells.

This overexpression is also related to the prognosis of the disease, with higher overexpression of CB2 in the most aggressive tumors (Calatozzolo et al., 2007; Ellert-Miklaszewska et al., 2007; Sánchez et al., 2001).

The action of cannabinoids on these receptors produces an antitumoral response against cancer cell growth, migration, angiogenesis and proliferation (Moreno et al., 2014).

However, this response does not affect non-tumor cells, making cannabinoids a safe cancer treatment (Rocha et al., 2014).

Studies in THC and synthetic CB2 agonists shown downregulation of MMP-2, cell invasion and cell viability (Blázquez et al., 2008; Galanti et al., 2008; Hernán Pérez de la Ossa et al., 2013).

CBD also showed anti cancer properties in several glioblastoma studies.

CBD modulates Id-1 gene and targets receptors CB1, CB2, TRPV-1 and TRPV-2 (Solinas et al., 2013; Soroceanu et al., 2013).

CBD has antiprolifetative and antiinvasive effects on glioblastoma cells and also promotes differentiation of glioblastoma steam cells (GSCs) and apoptosis process (Hernán Pérez de la Ossa et al., 2013; Nabissi et al., 2015).

In glioma xenografts 7.5 mg/kg/day CBD decreased tumor growth by about 20%. 7.5 mg/kg/day THC produced similar results and combined application of CBD and THC reduced tumor growth by approximately 50% suggesting synergy between both pathways (Torres et al., 2011).

In mice a combination of CBD and THC was found to work synergistically with radiation therapy to reduce tumor size (Scott et al., 2014). In human glioblastoma cell lines CBD reduces cancer cell viability and proliferation (Deng et al., 2016).

Importantly, CBD improves effectiveness of THC and is also effective in glioblastoma THC-resistant cells (Marcu et al., 2010; Solinas et al., 2013).

CBD also improves effectiveness of other anti cancer drugs as temozolomide, carmustine or dodorubicin through TRPV-2 receptor (Nabissi et al., 2013).

Literature:

Blázquez, C., Salazar, M., Carracedo, A., Lorente, M., Egia, A., González-Feria, L., Haro, A., Velasco, G., and Guzmán, M. (2008). cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. cancer Res. 68, 1945–1952.

Calatozzolo, C., Salmaggi, A., Pollo, B., Sciacca, F.L., Lorenzetti, M., Franzini, A., Boiardi, A., Broggi, G., and Marras, C. (2007). Expression of cannabinoid receptors and neurotrophins in human gliomas. Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol. 28, 304–310.

Deng, L., Ng, L., Ozawa, T., and Stella, N. (2016). Quantitative analyses of synergistic responses between cannabidiol and DNA-damaging agents on the proliferation and viability of glioblastoma and neural progenitor cells in culture. J. Pharmacol. Exp. Ther.

Ellert-Miklaszewska, A., Grajkowska, W., Gabrusiewicz, K., Kaminska, B., and Konarska, L. (2007). Distinctive pattern of cannabinoid receptor type II (CB2) expression in adult and pediatric brain tumors. Brain Res. 1137, 161–169.

Galanti, G., Fisher, T., Kventsel, I., Shoham, J., Gallily, R., Mechoulam, R., Lavie, G., Amariglio, N., Rechavi, G., and Toren, A. (2008). Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells. Acta Oncol. Stockh. Swed. 47, 1062–1070.

Hernán Pérez de la Ossa, D., Lorente, M., Gil-Alegre, M.E., Torres, S., García-Taboada, E., Aberturas, M.D.R., Molpeceres, J., Velasco, G., and Torres-Suárez, A.I. (2013). Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme. PloS One 8, e54795.

Marcu, J.P., Christian, R.T., Lau, D., Zielinski, A.J., Horowitz, M.P., Lee, J., Pakdel, A., Allison, J., Limbad, C., Moore, D.H., et al. (2010). Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol. cancer Ther. 9, 180–189.

Moreno, E., Andradas, C., Medrano, M., Caffarel, M.M., Pérez-Gómez, E., Blasco-Benito, S., Gómez-Cañas, M., Pazos, M.R., Irving, A.J., Lluís, C., et al. (2014). Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. J. Biol. Chem. 289, 21960–21972.

Nabissi, M., Morelli, M.B., Santoni, M., and Santoni, G. (2013). Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis 34, 48–57.

Nabissi, M., Morelli, M.B., Amantini, C., Liberati, S., Santoni, M., Ricci-Vitiani, L., Pallini, R., and Santoni, G. (2015). Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner. Int. J. cancer J. Int. cancer 137, 1855–1869.

Rocha, F.C.M., Santos Júnior, J.G. Dos, Stefano, S.C., and da Silveira, D.X. (2014). Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. J. Neurooncol. 116, 11–24.

Sánchez, C., de Ceballos, M.L., Gomez del Pulgar, T., Rueda, D., Corbacho, C., Velasco, G., Galve-Roperh, I., Huffman, J.W., Ramón y Cajal, S., and Guzmán, M. (2001). Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. cancer Res. 61, 5784–5789.

Scott, K.A., Dalgleish, A.G., and Liu, W.M. (2014). The Combination of Cannabidiol and Δ9-Tetrahydrocannabinol Enhances the Anticancer Effects of Radiation in an Orthotopic Murine Glioma Model. Mol. cancer Ther.

Solinas, M., Massi, P., Cinquina, V., Valenti, M., Bolognini, D., Gariboldi, M., Monti, E., Rubino, T., and Parolaro, D. (2013). Cannabidiol, a Non-Psychoactive cannabinoid Compound, Inhibits Proliferation and Invasion in U87-MG and T98G Glioma Cells through a Multitarget Effect. PLoS ONE 8.

Soroceanu, L., Murase, R., Limbad, C., Singer, E., Allison, J., Adrados, I., Kawamura, R., Pakdel, A., Fukuyo, Y., Nguyen, D., et al. (2013). Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target. cancer Res. 73, 1559–1569.

Stella, N. (2010). cannabinoid and cannabinoid-like receptors in microglia, astrocytes and astrocytomas. Glia 58, 1017–1030.

Torres, S., Lorente, M., Rodríguez-Fornés, F., Hernández-Tiedra, S., Salazar, M., García-Taboada, E., Barcia, J., Guzmán, M., and Velasco, G. (2011). A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol. cancer Ther. 10, 90–103.