钩吻化学成分UAE和ZCU抗肿瘤活性及作用机制研究
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摘要
钩吻为马钱科(Loganiacease)植物胡蔓藤(Gelsemium elegans Benth，GEB)的全草，是世界著名的剧毒植物，具有镇痛、抗肿瘤等作用。本文对钩吻非生物碱组分进行了分离和追踪，得到两个活性化合物：钩藤酸(uncarinic acid E，UAE)和3β-羟基-27-p-(E)-桂皮酰基齐墩果酸(3β-hydroxy-27-p-(Z)-coumaroyloxyursan-12-en-28-oic acid，ZCU)，并对其诱导HepG2和KB细胞死亡的机制进行了较为系统的研究。实验结果表明，钩吻非生物碱不同组分具有体内抗肿瘤作用，并能增加荷瘤小鼠的免疫功能，体内外毒性结果相一致。
研究发现UAE和ZCU抑制了几种肿瘤细胞的生长，其中包括：黑色素瘤细胞(A375-S2)，人乳腺癌细胞(MCF-7，包括抗药株)、人胃腺癌细胞(SGC-7901)，人口腔上皮癌KB细胞及人肝癌HepG2细胞。但UAE和ZCU对小鼠骨髓细胞和人外周血单核细胞均有促进增长作用，对人的正常脾细胞及诱导分化的T细胞和B细胞的生长影响较小，表明UAE和ZCU在具有抗肿瘤活性的同时，对正常细胞具有较低的毒性或有免疫增强作用。
在UAE诱导HepG2细胞死亡中，电镜和DNA片断化分析证明，UAE能够引起HepG2细胞凋亡。UAE激活了Caspase-3，-6，以Caspase特异性的方式劈开Caspase的底物PARP，Caspase-3裂解为活性物。LDH活力分析表明，UAE诱导的细胞死亡为凋亡和坏死同时存在，流式细胞结果也给出了相同的结论。UAE上调了p53蛋白的表达水平，阻滞细胞周期停滞在G0／G1期，上调了Bax蛋白的表达，同时下调了Bcl-2和Bcl-XL蛋白的表达，这与p53的激活密切相关。激活后的Bax引起了线粒体膜通透性的改变，促进了细胞色素c的释放，进而导致Caspase的激活，这一过程可被MEK的抑制剂PD98059和P13K抑制剂Wortmaninin阻止，表明ERK和p53为诱导细胞凋亡的中间重要环节；而PKC促进剂PMA能够反转UAE诱导的细胞死亡。
ZCU在诱导KB细胞死亡中，经历了经典的凋亡途径。Caspase抑制剂有效的阻止了ZCU诱导的细胞凋亡，而细胞坏死也同时发生。ZCU抑制了ERK的表达而激活了p38的表达，Wortmannin能有效抑制细胞死亡。形态学变化及DNA电泳都证明了ZCU能够诱导KB细胞的凋亡。p53积累及MARP家族中ERK抑制和p38激活引起了线粒体Bax与Bcl-xL，Bcl-2改变。表明ERK作用于p53的上游，p53和MAPK家族在细胞凋亡中起到重要作用。PKC可能是ZCU作用的上游蛋白。
综合UAE和ZCU对HepG_2和KB细胞作用结果的分析，UAE和ZCU诱导细胞凋亡的信号转导途径为：UAE和ZCU抑制了PLCγ1，减少了IP3和DAG的产生，引起PKC抑制，同时引起DNA损伤，进一步通过ATM途径和PI3K途径，分别激活p53和抑制Ras-Raf-MEK途径，引起线粒体膜Bax／Bcl-2和Bax／Bcl-xL比例改变，细胞色素c释放，激活Caspase-3，Caspase-6而引起Caspase级联反应，导致DNA断裂，细胞凋亡。同时ERK，p38与p53之间存在交互作用。
Graceful jessamine herb belongs to Gelsemium elegans Benth of Loganiaceae, Gelsemium elegans Benth has long been identified in Traditional Chinese Medicine to have broad spectrum of pharmacological activities, i.e. antitumor, analgesia, immunoregulation and acetylcholine-like effects. This dissertation reported that uncarinic acid E (UAE) and 3β-hydroxy-27-p- (Z)-coumaroyloxyursan-12 -en-28-oic acid (ZCU) were obtained from non-alkaloid components of Gelsemium elegans Benth through activity screening, and their molecular mechanisms of tumor cell apoptosis induced by UAE and ZCU in HepG2 and KB cell line were studied in vitro respectively. The results showed that different components of non-alkaloid of Gelsemium elegans Benth possessed effects of resisting tumor and immune function were enhanced on tumor-bearing mice in vivo. The toxicity were corresponded in vitro and in vivo.The studies demonstrate that UAE and ZCU significantly inhibited proliferation of several tumor cell lines, including human melanoma A375-S2, human mammary adenocarcinoma MCF-7 (including drug resistance strain drug resistance cell line), human gastric adenocarcinoma SGC-7901, human oral epithelioma KB and human hepatoma HepG2. Moreover, UAE and ZCU promoted proliferation for bone marrow (BMC) in mice and human peripheral blood mononuclear cells (PBMC), and showed minor cytotoxity against normal spleen cells and induced differentiation of T cells and B cell, suggesting that UAE and ZCU had anti-tumor activity and less side effects or immunologic enhancement on normal cells.In UAE-treated HepG2 cells, the results demonstrate that UAE could provoke HepG2 cells apoptosis demonstrated by transmission electron microscope and DNA fragmentation. UAE induced HepG2 cells to activate caspase-3, -6. Caspase substrate PARP was cleaved in a caspase-specific manner, and caspase-3 were cleaved to actives. LDH activity assay and flow cytometry demonstrated that apoptosis and necrosis were induced by UAE simultaneously. UAE also up-regulated p53 expression level in the apoptotic process of HepG2 cells, p53 mediated cell cycle arrest at G0/G1 phase in UAE-treated HepG2 cells. UAE increased the expression of the apoptosis inducer, Bax, decreased the expression of the anti-apoptotic protein, Bcl-x_L and Bcl-2, promoted the release of cytochrome c, and activated down-stream caspase-3 in mitochondrial apoptotic pathway. The mitochondrial apoptotic pathway positively correlated with elevated expression of p53 protein and ERK. This process was prevented by MEK inhibitor, PD98059, and PI3K inhibitor, wortmannin, indicating that ERK activated p53. PKC reactivator, PMA, reversed cell death induced by UAE.
In KB cells, ZCU initiated classic apoptotic pathways. Caspase inhibitors and MAPK inhibitors blocked ZCU-induced cell apoptosis. ZCU induced KB cells apoptosis and necrosis simultaneously. Moreover, ZCU inhibited the expression of ERK and up-regulated the expression of p38. ERK resulted in the up-regulation of p53 expression, which was blocked by MEK inhibitor PD98059, suggesting that ERK acted on the upstream of p53. Accumulation of p53, inhibition of ERK and activation of p38 increased the ratio of Bax/Bcl-x_L or Bax/Bcl-2 protein expression, and promoted the release of cytochrome c into cytosol, resulting in apoptotic cell death, at the same time, PKC plays an important regulatory role in the activation of MAPKs.
In summary, the pathways of signal transduction could be that UAE and ZCU inhibited phospholipase C_γ1, and then inhibited PKC, the up regulation of p53 induced by the down regulation of ERK due to PKC or PI3K inhibition. The up regulation of p53 changes the ratios of Bcl-2/Bax or Bcl-xL/Bax, then it induces the release of cytochrome c, followed by the amplification of caspase cascade reaction, finally leads cell to apoptosis.
研究发现UAE和ZCU抑制了几种肿瘤细胞的生长，其中包括：黑色素瘤细胞(A375-S2)，人乳腺癌细胞(MCF-7，包括抗药株)、人胃腺癌细胞(SGC-7901)，人口腔上皮癌KB细胞及人肝癌HepG2细胞。但UAE和ZCU对小鼠骨髓细胞和人外周血单核细胞均有促进增长作用，对人的正常脾细胞及诱导分化的T细胞和B细胞的生长影响较小，表明UAE和ZCU在具有抗肿瘤活性的同时，对正常细胞具有较低的毒性或有免疫增强作用。
在UAE诱导HepG2细胞死亡中，电镜和DNA片断化分析证明，UAE能够引起HepG2细胞凋亡。UAE激活了Caspase-3，-6，以Caspase特异性的方式劈开Caspase的底物PARP，Caspase-3裂解为活性物。LDH活力分析表明，UAE诱导的细胞死亡为凋亡和坏死同时存在，流式细胞结果也给出了相同的结论。UAE上调了p53蛋白的表达水平，阻滞细胞周期停滞在G0／G1期，上调了Bax蛋白的表达，同时下调了Bcl-2和Bcl-XL蛋白的表达，这与p53的激活密切相关。激活后的Bax引起了线粒体膜通透性的改变，促进了细胞色素c的释放，进而导致Caspase的激活，这一过程可被MEK的抑制剂PD98059和P13K抑制剂Wortmaninin阻止，表明ERK和p53为诱导细胞凋亡的中间重要环节；而PKC促进剂PMA能够反转UAE诱导的细胞死亡。
ZCU在诱导KB细胞死亡中，经历了经典的凋亡途径。Caspase抑制剂有效的阻止了ZCU诱导的细胞凋亡，而细胞坏死也同时发生。ZCU抑制了ERK的表达而激活了p38的表达，Wortmannin能有效抑制细胞死亡。形态学变化及DNA电泳都证明了ZCU能够诱导KB细胞的凋亡。p53积累及MARP家族中ERK抑制和p38激活引起了线粒体Bax与Bcl-xL，Bcl-2改变。表明ERK作用于p53的上游，p53和MAPK家族在细胞凋亡中起到重要作用。PKC可能是ZCU作用的上游蛋白。
综合UAE和ZCU对HepG_2和KB细胞作用结果的分析，UAE和ZCU诱导细胞凋亡的信号转导途径为：UAE和ZCU抑制了PLCγ1，减少了IP3和DAG的产生，引起PKC抑制，同时引起DNA损伤，进一步通过ATM途径和PI3K途径，分别激活p53和抑制Ras-Raf-MEK途径，引起线粒体膜Bax／Bcl-2和Bax／Bcl-xL比例改变，细胞色素c释放，激活Caspase-3，Caspase-6而引起Caspase级联反应，导致DNA断裂，细胞凋亡。同时ERK，p38与p53之间存在交互作用。
Graceful jessamine herb belongs to Gelsemium elegans Benth of Loganiaceae, Gelsemium elegans Benth has long been identified in Traditional Chinese Medicine to have broad spectrum of pharmacological activities, i.e. antitumor, analgesia, immunoregulation and acetylcholine-like effects. This dissertation reported that uncarinic acid E (UAE) and 3β-hydroxy-27-p- (Z)-coumaroyloxyursan-12 -en-28-oic acid (ZCU) were obtained from non-alkaloid components of Gelsemium elegans Benth through activity screening, and their molecular mechanisms of tumor cell apoptosis induced by UAE and ZCU in HepG2 and KB cell line were studied in vitro respectively. The results showed that different components of non-alkaloid of Gelsemium elegans Benth possessed effects of resisting tumor and immune function were enhanced on tumor-bearing mice in vivo. The toxicity were corresponded in vitro and in vivo.The studies demonstrate that UAE and ZCU significantly inhibited proliferation of several tumor cell lines, including human melanoma A375-S2, human mammary adenocarcinoma MCF-7 (including drug resistance strain drug resistance cell line), human gastric adenocarcinoma SGC-7901, human oral epithelioma KB and human hepatoma HepG2. Moreover, UAE and ZCU promoted proliferation for bone marrow (BMC) in mice and human peripheral blood mononuclear cells (PBMC), and showed minor cytotoxity against normal spleen cells and induced differentiation of T cells and B cell, suggesting that UAE and ZCU had anti-tumor activity and less side effects or immunologic enhancement on normal cells.In UAE-treated HepG2 cells, the results demonstrate that UAE could provoke HepG2 cells apoptosis demonstrated by transmission electron microscope and DNA fragmentation. UAE induced HepG2 cells to activate caspase-3, -6. Caspase substrate PARP was cleaved in a caspase-specific manner, and caspase-3 were cleaved to actives. LDH activity assay and flow cytometry demonstrated that apoptosis and necrosis were induced by UAE simultaneously. UAE also up-regulated p53 expression level in the apoptotic process of HepG2 cells, p53 mediated cell cycle arrest at G0/G1 phase in UAE-treated HepG2 cells. UAE increased the expression of the apoptosis inducer, Bax, decreased the expression of the anti-apoptotic protein, Bcl-x_L and Bcl-2, promoted the release of cytochrome c, and activated down-stream caspase-3 in mitochondrial apoptotic pathway. The mitochondrial apoptotic pathway positively correlated with elevated expression of p53 protein and ERK. This process was prevented by MEK inhibitor, PD98059, and PI3K inhibitor, wortmannin, indicating that ERK activated p53. PKC reactivator, PMA, reversed cell death induced by UAE.
In KB cells, ZCU initiated classic apoptotic pathways. Caspase inhibitors and MAPK inhibitors blocked ZCU-induced cell apoptosis. ZCU induced KB cells apoptosis and necrosis simultaneously. Moreover, ZCU inhibited the expression of ERK and up-regulated the expression of p38. ERK resulted in the up-regulation of p53 expression, which was blocked by MEK inhibitor PD98059, suggesting that ERK acted on the upstream of p53. Accumulation of p53, inhibition of ERK and activation of p38 increased the ratio of Bax/Bcl-x_L or Bax/Bcl-2 protein expression, and promoted the release of cytochrome c into cytosol, resulting in apoptotic cell death, at the same time, PKC plays an important regulatory role in the activation of MAPKs.
In summary, the pathways of signal transduction could be that UAE and ZCU inhibited phospholipase C_γ1, and then inhibited PKC, the up regulation of p53 induced by the down regulation of ERK due to PKC or PI3K inhibition. The up regulation of p53 changes the ratios of Bcl-2/Bax or Bcl-xL/Bax, then it induces the release of cytochrome c, followed by the amplification of caspase cascade reaction, finally leads cell to apoptosis.
引文
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