DIFFERENTIAL ANTIPROLIFERATIVE EFFECTS OF CANNABIDIOL (CBD) IN THE CORE AND INFILTRATIVE BOUNDARY OF HUMAN GLIOBLASTOMA CELLS

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Abstract
Background We have previously reported that the brain cannabinoid signalling pathways regulates in the isocitrade dehydrogenase-1 wild-type glioblastoma (GBM) core and infiltrative boundary tumor cell proliferation. To uncover the mechanism behind these effects we have investigated the possible antitumoral actions of cannabidiol (CBD) in the tumour core cells (U87) and the Glioma Invasive Margin cells (GIN-8), the latter representing a better proxy of post-surgical residual disease. Methods Monolayer of GBM cells cultures were treated with increasing concentrations of CBD, Temozolomide (TMZ), Carmustine (BCUN), Fluoxetine, Doxorubicine (DOX) or vehicle. After treatment, cell viability was assessed using an MTT kit assay to evaluate mitochondrial activity/cell proliferation, cytotoxicity was evaluated by LDH release. In addition, we have investigated the effects of the CBD alone or in combination with the above drugs on the autophagic cell death, unfold protein response (UPR) mitochondrial response and release of proinflammatory cytokines. Summary This study highlights the potential therapeutic relevance of CBD in combination with other FDA-approved drugs against glioblastoma. We observed strong synergism between CBD and TMZ, FX, and DOXO in reducing U87-MG cell viability in vitro, with even stronger synergy between CBD and TMZ in GIN-8 cells. Our preliminary data identify CBD as a potential anti-neoplastic drug in both core and invasive margin cells. Given the heterogeneity of glioblastoma, further studies will elucidate the molecular mechanisms underlying CBD observed anti-tumoral actions and determine whether it can potentially be used in the future as an addition to current therapies.

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