Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
J Pharm Pharmacol. 2020 Oct;72(10):1445-1457. doi: 10.1111/jphp.13327. Epub 2020 Jul 27.
Acridone alkaloids from Citrus and their derivatives show various kinds of biological activity. However, the anticancer activities of dimeric acridone alkaloids with unique structures and the molecular mechanism of these effects are poorly understood.
We investigated the cytotoxicity effects of dimeric acridone alkaloids isolated from Marsh grapefruit on human myeloid leukaemia HL-60 cells.
Of the six dimeric acridone alkaloids tested, citbismine-E, the most potent, dose- and time-dependently decreased HL-60 cell viability by inducing apoptosis. The treatment of HL-60 cells with citbismine-E yielded a significant increase in levels of intracellular reactive oxygen species (ROS). Citbismine-E lowered the mitochondrial membrane potential and increased the activities of caspase-9 and -3. In addition, citbismine-E-induced apoptosis, decrease in mitochondrial membrane potential and caspase activation were significantly alleviated by pretreatment of the cells with antioxidant N-acetylcysteine (NAC). Citbismine-E induced intrinsic caspase-dependent apoptosis through ROS-mediated c-Jun N-terminal kinase activation. Citbismine-E-induced production of oxidative stress biomarkers, malondialdehyde and 8-hydroxy-2'-deoxyguanosine was also attenuated by pretreatment with NAC.
Citbismine-E is a powerful cytotoxic agent against HL-60 cells that acts by inducing mitochondrial dysfunction-mediated apoptosis through ROS-dependent JNK activation. Citbismine-E also induced oxidative stress damage via ROS-mediated lipid peroxidation and DNA damage in HL-60 cells.
柑橘及其衍生物中的吖啶酮生物碱具有多种生物活性。然而，具有独特结构的二聚吖啶酮生物碱的抗癌活性及其作用机制尚不清楚。
我们研究了从 Marsh 葡萄柚中分离得到的二聚吖啶酮生物碱对人髓样白血病 HL-60 细胞的细胞毒性作用。
在所测试的六种二聚吖啶酮生物碱中，最有效的 citbismine-E 通过诱导细胞凋亡，剂量和时间依赖性地降低 HL-60 细胞活力。用 citbismine-E 处理 HL-60 细胞会导致细胞内活性氧（ROS）水平显著增加。Citbismine-E 降低了线粒体膜电位并增加了 caspase-9 和 -3 的活性。此外，用抗氧化剂 N-乙酰半胱氨酸（NAC）预处理细胞可显著减轻 citbismine-E 诱导的细胞凋亡、线粒体膜电位降低和 caspase 激活。Citbismine-E 通过 ROS 介导的 c-Jun N-末端激酶（JNK）激活诱导内在 caspase 依赖性细胞凋亡。用 NAC 预处理还可减轻 citbismine-E 诱导的氧化应激生物标志物丙二醛和 8-羟基-2'-脱氧鸟苷的产生。
Citbismine-E 是一种强大的 HL-60 细胞细胞毒性剂，通过 ROS 依赖性 JNK 激活诱导线粒体功能障碍介导的凋亡起作用。Citbismine-E 还通过 ROS 介导的脂质过氧化和 DNA 损伤在 HL-60 细胞中诱导氧化应激损伤。
