The Dr. Miriam and Sheldon G Adelson Center for the Biology of Addictive Diseases, Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Cell Death Dis. 2013 Dec 5;4(12):e949. doi: 10.1038/cddis.2013.471.
Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells. It is not an agonist of the classical CB1/CB2 cannabinoid receptors and the mechanism by which it functions is unknown. Here, we studied the effects of CBD on various mitochondrial functions in BV-2 microglial cells. Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death. Density gradient fractionation analysis by mass spectrometry and western blotting showed colocalization of CBD with protein markers of mitochondria. Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance. Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD. Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD. The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD.
大麻二酚（CBD）是一种非精神活性植物大麻素，可抑制癌细胞和活化免疫细胞的增殖并诱导其死亡。它不是经典的 CB1/CB2 大麻素受体的激动剂，其作用机制尚不清楚。在这里，我们研究了 CBD 对 BV-2 小胶质细胞中各种线粒体功能的影响。我们的研究结果表明，CBD 处理会导致细胞内钙离子水平呈双相增加，并导致线粒体功能和形态发生变化，从而导致细胞死亡。通过质谱和 Western blot 进行的密度梯度分级分析表明，CBD 与线粒体的蛋白标志物共定位。作为细胞能量、代谢稳态和凋亡中起作用的外线粒体膜蛋白电压依赖性阴离子通道 1（VDAC1）的单通道记录表明，CBD 明显降低了通道电导。最后，使用微尺度热泳动，我们显示了纯化的荧光标记的 VDAC1 和 CBD 之间的直接相互作用。因此，VDAC1 似乎是 CBD 的一种新型线粒体靶标。CBD 对 VDAC1 的抑制可能是 CBD 具有免疫抑制和抗癌作用的原因。
