Department of Biology, American University of Beirut, Beirut, Lebanon.
Cancer Biol Ther. 2008 Nov;7(11):1765-73. doi: 10.4161/cbt.7.11.6740. Epub 2008 Nov 5.
Lebanese sage essential oil possesses antitumor properties, however, the bioactive components and antitumor mechanisms are not known. Here we show that combining the three sage bioactive compounds, Linalyl acetate (Ly), Terpeniol (Te) and Camphor (Ca), caused synergistic inhibition of the growth of two isogenic human colon cancer cell lines HCT-116 (p53(+/+) and p53(-/-)) and had no effect on growth of FHs74Int normal human intestinal cell line. In p53(+/+) cells, the combination of Ly + Te + Ca (10(-3) M of each) caused significant accumulation of cells in PreG(1) (64% at 48 hours); less preG(1) increase was observed in response to Ly + Te (25%) or Ly + Ca (14%). In p53(-/-) cells, Ly + Te + Ca caused cell accumulation in PreG(1) and G(2)/M phases. In response to the three components, 58% apoptosis occurred in p53(+/+) cells and 38% in p53(-/-) cells. Apoptosis by Ly + Te + Ca, in p53+/+ cells, was associated with increased Bax/Bcl-2 ratio and pp53/p53 ratio, cleavage and activation of caspase-3, loss of mitochondrial membrane potential and cytochrome c release. In p53(-/-) cells, the disruption of mitochondrial membrane potential was observed but to a lesser extent than in p53(+/+) cells and caspase activation or cleavage did not appear to be involved in drug-induced apoptosis. Sage components induced poly(ADP-ribose)-polymerase (PARP) cleavage in both p53(+/+) and p53(-/-) cell lines. Pretreatment with the caspase-3 inhibitor and pan caspase inhibitor abrogated drug-mediated apoptosis and blocked procaspase-3 activation and partially blocked PARP cleavage in p53(+/+) cells. Conversely, in p53(-/-) cells, pre-incubation with caspase inhibitors potentiated drug-induced cell death. It appears that apoptosis in p53(+/+) cells is through the mitochondrial-mediated, caspase-dependent pathway, while in p53(-/-) cells apoptosis is mostly caspase independent despite the presence and features indicating caspase-dependent cell death, such as cytochrome c release and PARP cleavage. Our findings encourage further studies of sage oil components as promising chemotherapeutic agents against colon cancer.
迷迭香精油具有抗肿瘤特性，但生物活性成分和抗肿瘤机制尚不清楚。在这里，我们发现三种迷迭香生物活性化合物，乙酸芳樟酯（Ly）、萜品醇（Te）和樟脑（Ca）联合使用可协同抑制两种同源人结肠癌细胞系 HCT-116（p53（+/+）和 p53（-/-））的生长，而对正常人类肠细胞系 FHs74Int 没有影响。在 p53（+/+）细胞中，Ly + Te + Ca （每种浓度为 10（-3）M）的组合导致 PreG（1）期细胞的显著积累（48 小时时为 64%）；而 Ly + Te（25%）或 Ly + Ca（14%）的反应中，PreG（1）的增加较少。在 p53（-/-）细胞中，Ly + Te + Ca 导致细胞在 PreG（1）和 G（2）/M 期积累。三种成分的作用下，p53（+/+）细胞中发生 58%的细胞凋亡，p53（-/-）细胞中发生 38%的细胞凋亡。Ly + Te + Ca 在 p53（+/+）细胞中的凋亡与 Bax/Bcl-2 比值和 pp53/p53 比值增加、caspase-3 裂解和激活、线粒体膜电位丧失和细胞色素 c 释放有关。在 p53（-/-）细胞中，观察到线粒体膜电位破坏，但程度低于 p53（+/+）细胞，caspase 激活或裂解似乎不参与药物诱导的细胞凋亡。迷迭香成分在 p53（+/+）和 p53（-/-）细胞系中诱导多聚（ADP-核糖）-多聚酶（PARP）裂解。用 caspase-3 抑制剂和泛 caspase 抑制剂预处理可阻断药物介导的细胞凋亡，并阻止 p53（+/+）细胞中 procaspase-3 的激活和部分阻断 PARP 裂解。相反，在 p53（-/-）细胞中，caspase 抑制剂的预孵育增强了药物诱导的细胞死亡。似乎 p53（+/+）细胞中的细胞凋亡是通过线粒体介导的 caspase 依赖性途径，而 p53（-/-）细胞中的细胞凋亡主要是 caspase 非依赖性的，尽管存在表明 caspase 依赖性细胞死亡的特征，如细胞色素 c 释放和 PARP 裂解。我们的研究结果鼓励进一步研究迷迭香油成分作为治疗结肠癌的有前途的化疗药物。
