Spigarelli Renato, Spisni Enzo, Magalhães Mariana, Cabral Célia, Gonçalves Ana Cristina, Saracino Ilaria Maria, Botti Giada, Dalpiaz Alessandro, Beggiato Sarah, Valerii Maria Chiara
Department of Biological, Geological and Environmental Sciences, University of Bologna, Via Selmi 3, 40126 Bologna, Italy.
Institute for Interdisciplinary Research, Doctoral Programme in Experimental Biology and Biomedicine (PDBEB), University of Coimbra, 3030-789 Coimbra, Portugal.
Int J Mol Sci. 2024 Dec 30;26(1):238. doi: 10.3390/ijms26010238.
This study aimed to investigate β-Caryophyllene (BCA) pharmacokinetics as well as the potential antitumor activity and mechanism of action of BCA and eugenol (EU), alone or in combination, in U87 glioblastoma (GB) cells. The BCA pharmacokinetic was studied by evaluating its concentration profiles in rat blood and cerebrospinal fluid after oral and intravenous administration. EU and BCA antitumor mechanisms were assessed by comparing their effects in U87 GB cells and non-tumoral HMC3 cells. Cell death, cell cycle regulation and mitochondrial membrane potential (MMP) were evaluated using flow cytometry. mRNA levels of target genes were evaluated by qPCR. Secreted cytokines were measured by Luminex. BCA, as well as EU, permeates the brain. EU and BCA affected the viability and proliferation of U87 cells (up to 50%, < 0.001) but not HMC3 cells and showed a synergistic effect. BCA and EU induced G0/G1 cell cycle arrest, increasing apoptosis/necrosis. EU and BCA induced the downregulation of mRNAs encoding for key proteins involved in GB angiogenesis (VEGFA decreased op to 60%, < 0.01), proliferation and progression, and showed anti-inflammatory activity (IL-4 significantly decreased, < 0.001). EU and BCA demonstrated strong and multitarget antitumor activity in U87 cells. Our results provide a strong rationale for the further evaluation of EU and BCA as possible therapeutic molecules in GB management.
本研究旨在调查β-石竹烯（BCA）的药代动力学，以及BCA和丁香酚（EU）单独或联合使用对U87胶质母细胞瘤（GB）细胞的潜在抗肿瘤活性和作用机制。通过评估口服和静脉给药后大鼠血液和脑脊液中的浓度曲线来研究BCA的药代动力学。通过比较EU和BCA对U87 GB细胞和非肿瘤性HMC3细胞的作用来评估其抗肿瘤机制。使用流式细胞术评估细胞死亡、细胞周期调控和线粒体膜电位（MMP）。通过qPCR评估靶基因的mRNA水平。通过Luminex检测分泌的细胞因子。BCA以及EU均可透过血脑屏障。EU和BCA影响U87细胞的活力和增殖（高达50%，<0.001），但不影响HMC3细胞，并显示出协同作用。BCA和EU诱导G0/G1期细胞周期阻滞，增加细胞凋亡/坏死。EU和BCA诱导参与GB血管生成（VEGFA降低高达60%，<0.01）、增殖和进展的关键蛋白编码mRNA的下调，并显示出抗炎活性（IL-4显著降低，<0.001）。EU和BCA在U87细胞中表现出强大的多靶点抗肿瘤活性。我们的结果为进一步评估EU和BCA作为GB治疗中可能的治疗分子提供了有力的理论依据。
