Abstract
Simple SummaryGlioblastoma multiforme (GBM) is the most frequent, invasive, and lethal subtype of glioma brain tumors. Cannabis is commonly used for medical treatment, and individual phytocannabinoids have been shown to trigger GBM cell death. However, cannabis contains hundreds of different compounds, and the optimal combinations of molecules with anti-GBM activity are unknown. Here, we identified fractions from a cannabis strain that substantially reduced human GBM cell viability and motility. The fractions also reduced the ability of GBM cells to form colonies in 2 and 3-dimensional models, suggesting that the cannabis treatments may have the potential for preventing the formation of GBM neurospheres associated with the high resistance to current therapies. Importantly, these compounds also induced cell death in glioma stem cells derived from tumor specimens. The effectiveness of the fractions and combinations of cannabis compounds should be examined in GBM pre-clinical studies and clinical trials.Glioblastoma multiforme (GBM) is the most lethal subtype of glioma. Cannabis sativa is used for the treatment of various medical conditions. Around 150 phytocannabinoids have been identified in C. sativa, among them Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) that trigger GBM cell death. However, the optimal combinations of cannabis molecules for anti-GBM activity are unknown. Chemical composition was determined using high-performance liquid chromatography (HPLC) and gas chromatography mass spectrometry (GC/MS). Cytotoxic activity was determined by XTT and lactate dehydrogenase (LDH) assays and apoptosis and cell cycle by fluorescence-activated cell sorting (FACS). F-actin structures were observed by confocal microscopy, gene expression by quantitative PCR, and cell migration and invasion by scratch and transwell assays, respectively. Fractions of a high-THC cannabis strain extract had significant cytotoxic activity against GBM cell lines and glioma stem cells derived from tumor specimens. A standard mix (SM) of the active fractions F4 and F5 induced apoptosis and expression of endoplasmic reticulum (ER)-stress associated-genes. F4 and F5 inhibited cell migration and invasion, altered cell cytoskeletons, and inhibited colony formation in 2 and 3-dimensional models. Combinations of cannabis compounds exert cytotoxic, anti-proliferative, and anti-migratory effects and should be examined for efficacy on GBM in pre-clinical studies and clinical trials.
Highlights
Glioma are primary brain tumors that arise from glial cells and account for ~80% of all malignant brain tumors [1]
The methanol extract of high-THC C. sativa strain Dairy Queen (DQ) was found to be cytotoxic to the Glioblastoma multiforme (GBM) A172 cell line (Figure 1a), with a calculated IC50 of 10.17 μg/mL following treatment for 48 h (Figure 1b)
To identify the active compounds of the DQ extract, fractionation was performed using flash chromatography (Figure 1c), and the cytotoxic activity of fractions was examined on the A172 cell line
Summary
Glioma are primary brain tumors that arise from glial cells and account for ~80% of all malignant brain tumors [1]. According to the World Health Organization (WHO) classification, gliomas are classified from grade I (benign) to IV (malignant) [1]. They are classified according to molecular parameters that define the tumor entity [2]. Standard GBM therapies include maximal surgical resection followed by radio- and chemotherapy [3]. GSCs have been implicated in tumor infiltration and resistance to radio- and chemotherapy as well as tumor recurrence. These characteristics contribute to the high resistance of GBM cells to current standard therapies [6]. Effective therapies are urgently needed to improve the prognosis and quality of life for GBM patients
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