Hesperidin from Citrus seed induces human hepatocellular carcinoma HepG2 cell apoptosis via both mitochondrial and death receptor pathways.
Hesperidin from Citrus seed induces human hepatocellular carcinoma HepG2 cell apoptosis via both mitochondrial and death receptor pathways.
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DOI：
10.1007/s13277-015-3774-7
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Kongtawelert P
中科院分区：
文献类型：
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作者：
Banjerdpongchai R;Wudtiwai B;Khaw-On P;Rachakhom W;Duangnil N;Kongtawelert P
柑橘种子富含酚类化合物，如类黄酮。本研究的目的是鉴定柑橘籽提取物中黄酮类化合物的类型，以及柑橘籽提取物对人肝癌HepG 2细胞的细胞毒作用、细胞死亡方式和信号通路。黄酮类化合物具有抗癌、清除自由基和抗氧化活性。从柑桔籽提取物中鉴定出新橙皮苷、橙皮苷和柚皮苷等活性黄酮苷。三种化合物的细胞毒性作用呈剂量依赖性，并测定了IC 50水平。人肝癌细胞株HepG 2对橙皮苷、柚皮苷、新橙皮苷、柚皮素的敏感性依次为：橙皮苷>柚皮苷>新橙皮苷>柚皮素。橙皮苷诱导HepG 2细胞发生凋亡的剂量依赖性的方式证明了磷脂酰丝氨酸的外化和确定的膜联蛋白V-异硫氰酸荧光素和碘化丙啶染色，使用流式细胞术。用2′，7 ′-二氯氢荧光素二乙酸酯和流式细胞术检测橙皮苷对活性氧的产生无诱导作用。用3，3 ′-二己基氧碳菁碘化物流式细胞仪检测，橙皮苷处理后HepG 2细胞线粒体跨膜电位降低的细胞数呈浓度依赖性增加。Caspase-9、Caspase-8和Caspase-3活性在橙皮苷处理的HepG 2细胞中被激活并增加。Bcl-xL蛋白下调，而Bax，巴克，和tBid蛋白水平上调后，与橙皮苷的剂量依赖性的方式处理。结论：柑橘种子中的黄酮类化合物橙皮苷通过线粒体途径和死亡受体途径诱导人肝癌细胞HepG 2凋亡。柑橘籽黄酮类化合物是有益的，可开发为抗癌药物或食品添加剂，但仍需要进一步的动物和人体体内研究。
Citrus seeds are full of phenolic compounds, such as flavonoids. The aims of this study were to identify the types of flavonoids in Citrus seed extracts, the cytotoxic effect, mode of cell death, and signaling pathway in human hepatic cancer HepG2 cells. The flavonoids contain anticancer, free radical scavenging, and antioxidant activities. Neohesperidin, hesperidin, and naringin, active flavanone glycosides, were identified in Citrus seed extract. The cytotoxic effect of three compounds was in a dose-dependent manner, and IC50 levels were determined. The sensitivity of human HepG2 cells was as follows: hesperidin > naringin > neohesperidin > naringenin. Hesperidin induced HepG2 cells to undergo apoptosis in a dose-dependent manner as evidenced by the externalization of phosphatidylserine and determined by annexin V-fluorescein isothiocyanate and propidium iodide staining using flow cytometry. Hesperidin did not induce the generation of reactive oxygen species, which was determined by using 2′,7′-dichlorohydrofluorescein diacetate and flow cytometry method. The number of hesperidin-treated HepG2 cells with the loss of mitochondrial transmembrane potential increased concentration dependently, using 3,3′-dihexyloxacarbocyanine iodide employing flow cytometry. Caspase-9, -8, and -3 activities were activated and increased in hesperidin-treated HepG2 cells. Bcl-xL protein was downregulated whereas Bax, Bak, and tBid protein levels were upregulated after treatment with hesperidin in a dose-dependent manner. In conclusion, the bioflavanone from Citrus seeds, hesperidin, induced human HepG2 cell apoptosis via mitochondrial pathway and death receptor pathway. Citrus seed flavonoids are beneficial and can be developed as anticancer drug or food supplement, which still needs further in vivo investigation in animals and human beings.