Antiproliferative activity of endocannabinoids in U87‐MG glioblastoma cells

Abstract

Anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) are compounds naturally produced in humans and animals that interact with the cannabinoid system. These compounds activate specific cannabinoid receptors on cells to alter the neurotransmitter release from presynaptic neuron. There are studies which claim that endocannabinoids are selective towards tumor cells without affecting the functioning of normal cells, mainly by regulating different cell‐death pathways and downstream signaling molecules. The purpose of this study is to evaluate the antiproliferative activity of AEA and 2‐AG in U87‐MG glioblastoma cells. A cell viability assay utilizing 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium (MTS) was performed to evaluate the antiproliferative effects. The results demonstrated that AEA at concentrations 10 and 30 μM decreased cell viability as compared to control (P≤ 0.001). 2‐arachidonoylglycerol at concentrations 10, 30 and 100 μM decreased cell viability as compared to control (P≤ 0.001). Interestingly, a combination of AEA and 2‐AG at concentrations 10 and 30 μM, respectively reduced cell viability as compared to their individual effects suggesting a synergistic approach. Moreover, a significant reduction in cell viability was observed with a combination of OL‐135, a reversible inhibitor of fatty acid amide hydrolase (FAAH) and AEA as compared to AEA alone. Similarly, a significant reduction in cell viability was observed with a combination of JZL‐184, an irreversible inhibitor for monoacylglycerol lipase (MAGL) and 2‐AG as compared to 2‐AG alone. These results suggest that by inhibiting the enzymes FAAH and MAGL which are involved in the degradation of AEA and 2‐AG, respectively a further reduction in cell viability could be observed, suggesting a strategy to inhibit endocannabinoid degrading enzymes and use of endocannabinoids as potential anti‐cancer agents. Further assays will be performed to determine the mechanism of anti‐cancer activity demonstrated by these compounds.