Department of Molecular, Cellular & Developmental Biology, University of Colorado Boulder, Boulder, Colorado, USA.
Department of Biochemistry, University of Colorado Boulder, Boulder, Colorado, USA.
Mol Cell Proteomics. 2022 Oct;21(10):100262. doi: 10.1016/j.mcpro.2022.100262. Epub 2022 Jun 24.
The nonpsychoactive cannabinoid, cannabidiol (CBD), is Food and Dug Administration approved for treatment of two drug-resistant epileptic disorders and is seeing increased use among the general public, yet the mechanisms that underlie its therapeutic effects and side-effect profiles remain unclear. Here, we report a systems-level analysis of CBD action in human cell lines using temporal multiomic profiling. FRET-based biosensor screening revealed that CBD elicits a sharp rise in cytosolic calcium, and activation of AMP-activated protein kinase in human keratinocyte and neuroblastoma cell lines. CBD treatment leads to alterations in the abundance of metabolites, mRNA transcripts, and proteins associated with activation of cholesterol biosynthesis, transport, and storage. We found that CBD rapidly incorporates into cellular membranes, alters cholesterol accessibility, and disrupts cholesterol-dependent membrane properties. Sustained treatment with high concentrations of CBD induces apoptosis in a dose-dependent manner. CBD-induced apoptosis is rescued by inhibition of cholesterol synthesis and potentiated by compounds that disrupt cholesterol trafficking and storage. Our data point to a pharmacological interaction of CBD with cholesterol homeostasis pathways, with potential implications in its therapeutic use.
非精神活性大麻素大麻二酚（CBD）已获得美国食品药品监督管理局（FDA）批准，用于治疗两种耐药性癫痫疾病，在普通民众中的使用也越来越多，但它的治疗效果和副作用特征的潜在机制仍不清楚。在这里，我们使用时间多组学分析报告了 CBD 在人类细胞系中的作用的系统水平分析。FRET 生物传感器筛选显示，CBD 在人角质形成细胞和神经母细胞瘤细胞系中引起细胞质钙急剧上升和 AMP 激活蛋白激酶的激活。CBD 处理导致与胆固醇生物合成、运输和储存激活相关的代谢物、mRNA 转录物和蛋白质的丰度发生改变。我们发现 CBD 可快速掺入细胞膜，改变胆固醇的可及性，并破坏胆固醇依赖性膜特性。高浓度 CBD 的持续治疗以剂量依赖的方式诱导细胞凋亡。抑制胆固醇合成可挽救 CBD 诱导的细胞凋亡，而破坏胆固醇运输和储存的化合物可增强其作用。我们的数据表明 CBD 与胆固醇稳态途径存在药理学相互作用，这可能对其治疗用途有影响。
