δ-榄香烯抗肿瘤作用及诱导肿瘤凋亡的机制研究
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摘要
榄香烯(elemene)是从姜科植物温莪术的挥发油中经减压蒸馏获得的以β-榄香烯为主要成分的萜烯类化合物，属国家二类非细胞毒性抗肿瘤药物。GC-MS检测证实温莪术油中含有三种榄香烯：β-榄香烯、γ-榄香烯和δ-榄香烯。郭永钿等已从中分离出活性成分β-榄香烯和γ-榄香烯。最近我们成功的从榄香烯里分离出δ-榄香烯，但对于δ-榄香烯的抗肿瘤作用研究几乎未见报道。本文对δ-榄香烯的抗肿瘤作用及其机制进行了较为深入地研究。
体外细胞培养结果表明：δ-榄香烯对肿瘤细胞的抑制作用与癌细胞种类有关，其对HeLa、NCI-H292、HepG_2、DLD-1及HL-60细胞的IC_(50)分别为157.9、233.2、231.6、222.4、154.5μM。δ-榄香烯对SGC-7901和MCF细胞的影响较小。对正常小鼠骨髓细胞和人正常肝细胞WRL68抑制作用的考察，未发现δ-榄香烯对正常细胞的增殖有明显影响。人癌裸鼠异种移植肿瘤模型中，δ-榄香烯对实体型肝癌HepG_2呈剂量依赖性生长抑制作用，相同剂量下δ-榄香烯同β-榄香烯作用相似，组间相比无显著性意义(p＞0.05)；各给药组对荷瘤裸鼠的体重均无显著影响，说明δ-榄香烯对肿瘤的抑制作用是非细胞毒性的。扫描电镜结果显示δ-榄香烯所作用的瘤组织呈现明显的凋亡特征。
因此，对δ-榄香烯极敏感的HeLa、NCI-H292、DLD-1及HL-60细胞进行体外凋亡机制的研究。通过形态学方法、DNA fragmentation ELISA法、Annexin V-FITC和JC-1标记的流式细胞检测法、caspase-3活性检测法，均证实δ-榄香烯以凋亡的方式诱导这些瘤细胞死亡。进一步机制研究表明，δ-榄香烯能提高Bax／Bcl-2蛋白的比例，抑凋亡蛋白Bcl-w和Bcl-2表达降低；同时细胞外ERK1／2和p38表达增加，JNK的表达受抑制，线粒体膜电位降低，从线粒体内释放大量的cyto c和AIF，引起caspase级联反应，激活caspase-3，导致DNA断裂，激活以线粒体为中心的信号转导通路而诱导细胞凋亡。同时，ROS参与了δ-榄香烯诱导的凋亡过程。另外，δ-榄香烯可能对HL-60产生周期性阻滞，使细胞周期停滞于G_2／M期。
Elemene is a naturally occurring compound that can be isolated from the traditional Chinese medicinal herb, Curcuma Wenyujin, which was used to treat tumors in Chinese folk medicine. Elemene exists as an essential oil mixture ofβ-,γ- andδ-elemene.δ-elemene is another isomeric compound ofβ-elemene with a different site of double bond.The antitumor effect ofδ-elemene was investigated in vitro and in vivo, and the mechanism ofδ-elemene induced apoptosis in HeLa, NCI-H292, HL-60 or DLD-1 cell lines were reported in this dissertation.In vitro, we examined the inhibition ofδ-elemene on 7 tumor cell lines. There were five cell lines sensitive toδ-elemene, the values of IC_(50) were 157.9, 233.2, 231.6, 222.4, 154.5μM in HeLa, NCI-H292, HepG_2, DLD-1 and HL-60, respectively. We examined the effect ofδ-elemene on normal bone marrow and normal liver cell lines WRL68, it was suggested thatδ-elemene posseed no signs of bone marrow suppression and WRL68. In vivo, the HepG_2 cells were transplanted subcutaneously to BALB/c nude mice to produe solid tumors. The result was shown that the inhibition of HepG_2 treated withδ-elemene was in dose-dependent manner. There was no significant difference betweenδ-elemene andβ-elemene with the concentration of 75 mg/kg (p>0.05). And no significant reduction in body weight was found inδ-elemene treated mice, it meant that the inhibition to the growth of tumor was not cytotoxicity. Scanning electron micrographs further certificated thatδ-elemene inhibited the growth of HepG_2 by apoptosis in vivo.Therefore, the mechanism ofδ-elemene induced apoptosis in HeLa, NCI-H292, HL-60 or DLD-1 cell lines were investigated. Induction of early apoptosis byδ-elemene in a time-dependent manner was confirmed by morphology, DNA fragmentation ELISA assay, Annexin-V and JC-1 labeled flow cytometry analysis, and active caspase-3 assay.δ-elemene increased the expression of pro-apoptotic protein, Bax and decreased the expression of anti-apoptotic mitochondrial protein, Bcl-2. Activation of ERK1/2 and p38 and inhibition of JNK increased the ration of Bax/Bcl-2 protein expression. And the reduction in the mitochrome membrane potential was observed, and a release of cytochrome c and apoptosis inducing factor (AIF) from mitochrome into the cytosol occurred. And the activation of caspase-3 and cleaved PARP which prevented the DNA repair. These results indicated that the apoptosis induced byδ-elemene was through the mitochrome-mediated pathway. The rapid increase in intracellular reactive oxygen species (ROS) levels was involved in the mechanism of apoptosis. In addition, the G_2 block was involved in HL-60 cell death induced byδ-elemene.
体外细胞培养结果表明：δ-榄香烯对肿瘤细胞的抑制作用与癌细胞种类有关，其对HeLa、NCI-H292、HepG_2、DLD-1及HL-60细胞的IC_(50)分别为157.9、233.2、231.6、222.4、154.5μM。δ-榄香烯对SGC-7901和MCF细胞的影响较小。对正常小鼠骨髓细胞和人正常肝细胞WRL68抑制作用的考察，未发现δ-榄香烯对正常细胞的增殖有明显影响。人癌裸鼠异种移植肿瘤模型中，δ-榄香烯对实体型肝癌HepG_2呈剂量依赖性生长抑制作用，相同剂量下δ-榄香烯同β-榄香烯作用相似，组间相比无显著性意义(p＞0.05)；各给药组对荷瘤裸鼠的体重均无显著影响，说明δ-榄香烯对肿瘤的抑制作用是非细胞毒性的。扫描电镜结果显示δ-榄香烯所作用的瘤组织呈现明显的凋亡特征。
因此，对δ-榄香烯极敏感的HeLa、NCI-H292、DLD-1及HL-60细胞进行体外凋亡机制的研究。通过形态学方法、DNA fragmentation ELISA法、Annexin V-FITC和JC-1标记的流式细胞检测法、caspase-3活性检测法，均证实δ-榄香烯以凋亡的方式诱导这些瘤细胞死亡。进一步机制研究表明，δ-榄香烯能提高Bax／Bcl-2蛋白的比例，抑凋亡蛋白Bcl-w和Bcl-2表达降低；同时细胞外ERK1／2和p38表达增加，JNK的表达受抑制，线粒体膜电位降低，从线粒体内释放大量的cyto c和AIF，引起caspase级联反应，激活caspase-3，导致DNA断裂，激活以线粒体为中心的信号转导通路而诱导细胞凋亡。同时，ROS参与了δ-榄香烯诱导的凋亡过程。另外，δ-榄香烯可能对HL-60产生周期性阻滞，使细胞周期停滞于G_2／M期。
Elemene is a naturally occurring compound that can be isolated from the traditional Chinese medicinal herb, Curcuma Wenyujin, which was used to treat tumors in Chinese folk medicine. Elemene exists as an essential oil mixture ofβ-,γ- andδ-elemene.δ-elemene is another isomeric compound ofβ-elemene with a different site of double bond.The antitumor effect ofδ-elemene was investigated in vitro and in vivo, and the mechanism ofδ-elemene induced apoptosis in HeLa, NCI-H292, HL-60 or DLD-1 cell lines were reported in this dissertation.In vitro, we examined the inhibition ofδ-elemene on 7 tumor cell lines. There were five cell lines sensitive toδ-elemene, the values of IC_(50) were 157.9, 233.2, 231.6, 222.4, 154.5μM in HeLa, NCI-H292, HepG_2, DLD-1 and HL-60, respectively. We examined the effect ofδ-elemene on normal bone marrow and normal liver cell lines WRL68, it was suggested thatδ-elemene posseed no signs of bone marrow suppression and WRL68. In vivo, the HepG_2 cells were transplanted subcutaneously to BALB/c nude mice to produe solid tumors. The result was shown that the inhibition of HepG_2 treated withδ-elemene was in dose-dependent manner. There was no significant difference betweenδ-elemene andβ-elemene with the concentration of 75 mg/kg (p>0.05). And no significant reduction in body weight was found inδ-elemene treated mice, it meant that the inhibition to the growth of tumor was not cytotoxicity. Scanning electron micrographs further certificated thatδ-elemene inhibited the growth of HepG_2 by apoptosis in vivo.Therefore, the mechanism ofδ-elemene induced apoptosis in HeLa, NCI-H292, HL-60 or DLD-1 cell lines were investigated. Induction of early apoptosis byδ-elemene in a time-dependent manner was confirmed by morphology, DNA fragmentation ELISA assay, Annexin-V and JC-1 labeled flow cytometry analysis, and active caspase-3 assay.δ-elemene increased the expression of pro-apoptotic protein, Bax and decreased the expression of anti-apoptotic mitochondrial protein, Bcl-2. Activation of ERK1/2 and p38 and inhibition of JNK increased the ration of Bax/Bcl-2 protein expression. And the reduction in the mitochrome membrane potential was observed, and a release of cytochrome c and apoptosis inducing factor (AIF) from mitochrome into the cytosol occurred. And the activation of caspase-3 and cleaved PARP which prevented the DNA repair. These results indicated that the apoptosis induced byδ-elemene was through the mitochrome-mediated pathway. The rapid increase in intracellular reactive oxygen species (ROS) levels was involved in the mechanism of apoptosis. In addition, the G_2 block was involved in HL-60 cell death induced byδ-elemene.
引文
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