几种中药抗癌活性成分的分离鉴定及其诱导肿瘤细胞凋亡的机制研究
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摘要
天然产物是新药开发研究的重要源泉,中草药是我国传统医药发展的重要宝藏。系统地挖掘和整理中草药中的活性物质,是我国中药现代化的必由之路。本文选择了3种使用频率较高的抗癌中药—栝楼、穿心莲及白花蛇舌草,运用体外抗肿瘤模型解析和鉴定了3种抗肿瘤活性最为突出的单体化合物。对于肿瘤的治疗,本文分别从单体化合物抑制肿瘤增殖、联合用药提升抗肿瘤疗效及对耐药性肿瘤的治疗三方面进行研究,其结果如下:
论文首先运用抗肿瘤细胞活性跟踪实验,通过新型高通量逆流色谱和制备色谱技术分离纯化和鉴定了3种抗肿瘤效果最为显著的化合物单体—23,24-二氢葫芦素B,穿心莲内酯及熊果酸。
其次运用多种类型人肿瘤细胞株系模型,确定23,24-二氢葫芦素B可通过时间及剂量依赖性的方式抑制Bcap37等6株肿瘤细胞的体外增殖,并能通过阻滞Bcap37细胞于G＿2/M期,发生DNA片段化、caspase激酶活性升高及细胞色素c从线粒体释放至细胞质等现象,最终导致Bcap37细胞发生线粒体通路介导—caspase依赖的细胞凋亡。
本论文从中药配伍能提高肿瘤治疗效果得到提示,结合体外抗肿瘤模型实验结果,将穿心莲内酯与5-FU进行联合用药,实验结果证明在线粒体膜电位下降的同时,复方化合物通过提高Bax,p53的表达及caspase-8的活性,大幅度提高了caspase-8依赖的线粒体途径诱导的细胞凋亡率,从而显著降低了肿瘤细胞的存活率。
论文最后利用R-HepG2这一肝癌耐药株模型对熊果酸的耐药性及其相关的分子机制作了较为深入的研究,结果阐明熊果酸通过时间及剂量依赖性的方式抑制多药耐药株肿瘤细胞R-HepG2的体外增殖,并用实验证明该结果是通过caspase非依赖的凋亡诱导作用实现的,通过免疫荧光及siRNA实验,进一步证实了熊果酸诱导的细胞凋亡主要是通过AIF完成的,并伴有线粒体相关蛋白Bak的激活。动物实验结果表明,熊果酸能有效抑制R-HepG2肿瘤细胞在体内的增殖,并且对小鼠的机体基本无伤害,而且进一步证明该体内肿瘤抑制作用同样是通过AIF途径实现的。
In this work, three compounds were isolated from different Chinese medicine herbs. The potential effects of these compounds on anticancer were investigation-single compound therapy、combination therapy and drug resistant therapy. The results were summarized as follows:
By bioassay-guided fractionation procedure using human tumor cell lines led to the isolation of several compounds from Chinese herb medicine which possesses clear antitumor activity were isolated. Among them, three compounds with significant anticancer activity were found. Structure elucidation of them have been identified as 23,24-dihydrocucurbitacin (DHCB), andrographolide (ANDRO), ursolic acid (UA) respectively. All of them showed clear cytotoxicity against human tumor cell lines.
At first, we found DHCB could inhibit the proliferation of human cancer cell lines including Bcap37, HeLa, SW620, SMMC-7721, K562 and MCF-7 in a dose- and time-dependent manner, and induce G_2/M phase cell cycle arrest and apoptosis in human breast cancer cell line Bcap37 at low concentration. DHCB-induced Bcap37 apoptosis was characterized with the changes in nuclear morphology, DNA fragmentation, activation of caspase-like activities, poly(ADP-ribose) polymerase cleavage, release of cytochrome c into cytosol. Furthermore, the results suggest that DHCB-induced Bcap37 apoptosis through mitochondria-mediated caspase-dependent pathway.
Through the experiments, we can conclude that ANDRO has been shown to suppress the growth of HCC cells and trigger apoptosis in vitro. Most important, ANDRO potentiates the cytotoxic effect of 5-FU in HCC cell line SMMC-7721 through apoptosis. The addition of ANDRO to 5-FU induces synergistic apoptosis, which could be corroborated to the increased caspase-8, p53 activity and the significant changes of Bax conformation in these cells, resulting in increased losses of mitochondrial membrane potential, increased release of cytochrome c, and activation of caspase-9 and caspase-3. The results suggest that ANDRO may be effective in combination with 5-FU for the treatment of HCC cells.
To investigate the anti-resistant ability and its molecular mechanisms of the UA, we used multidrug resistant human hepatoma cell line (R-HepG2) as a test model. The results demonstrated that the UA could inhibit the proliferation of multidrug resistant human hepatoma R-HepG2 cells through apoptosis. Furthermore, The death of R-HepG2 cells induced by UA was mainly through the caspase-independent AIF signaling pathway with the participation of Bak. And we also showed that UA was effective against R-HepG2 cells in animal study with negligible body weight loss and damage towards the liver, heart and spleen. Most importantly, immunohistochemical staining in animal tissues also suggested that UA significantly inhibited the growth of R-HepG2 cells in nude mice was also through the AIF signaling pathway.
论文首先运用抗肿瘤细胞活性跟踪实验,通过新型高通量逆流色谱和制备色谱技术分离纯化和鉴定了3种抗肿瘤效果最为显著的化合物单体—23,24-二氢葫芦素B,穿心莲内酯及熊果酸。
其次运用多种类型人肿瘤细胞株系模型,确定23,24-二氢葫芦素B可通过时间及剂量依赖性的方式抑制Bcap37等6株肿瘤细胞的体外增殖,并能通过阻滞Bcap37细胞于G＿2/M期,发生DNA片段化、caspase激酶活性升高及细胞色素c从线粒体释放至细胞质等现象,最终导致Bcap37细胞发生线粒体通路介导—caspase依赖的细胞凋亡。
本论文从中药配伍能提高肿瘤治疗效果得到提示,结合体外抗肿瘤模型实验结果,将穿心莲内酯与5-FU进行联合用药,实验结果证明在线粒体膜电位下降的同时,复方化合物通过提高Bax,p53的表达及caspase-8的活性,大幅度提高了caspase-8依赖的线粒体途径诱导的细胞凋亡率,从而显著降低了肿瘤细胞的存活率。
论文最后利用R-HepG2这一肝癌耐药株模型对熊果酸的耐药性及其相关的分子机制作了较为深入的研究,结果阐明熊果酸通过时间及剂量依赖性的方式抑制多药耐药株肿瘤细胞R-HepG2的体外增殖,并用实验证明该结果是通过caspase非依赖的凋亡诱导作用实现的,通过免疫荧光及siRNA实验,进一步证实了熊果酸诱导的细胞凋亡主要是通过AIF完成的,并伴有线粒体相关蛋白Bak的激活。动物实验结果表明,熊果酸能有效抑制R-HepG2肿瘤细胞在体内的增殖,并且对小鼠的机体基本无伤害,而且进一步证明该体内肿瘤抑制作用同样是通过AIF途径实现的。
In this work, three compounds were isolated from different Chinese medicine herbs. The potential effects of these compounds on anticancer were investigation-single compound therapy、combination therapy and drug resistant therapy. The results were summarized as follows:
By bioassay-guided fractionation procedure using human tumor cell lines led to the isolation of several compounds from Chinese herb medicine which possesses clear antitumor activity were isolated. Among them, three compounds with significant anticancer activity were found. Structure elucidation of them have been identified as 23,24-dihydrocucurbitacin (DHCB), andrographolide (ANDRO), ursolic acid (UA) respectively. All of them showed clear cytotoxicity against human tumor cell lines.
At first, we found DHCB could inhibit the proliferation of human cancer cell lines including Bcap37, HeLa, SW620, SMMC-7721, K562 and MCF-7 in a dose- and time-dependent manner, and induce G_2/M phase cell cycle arrest and apoptosis in human breast cancer cell line Bcap37 at low concentration. DHCB-induced Bcap37 apoptosis was characterized with the changes in nuclear morphology, DNA fragmentation, activation of caspase-like activities, poly(ADP-ribose) polymerase cleavage, release of cytochrome c into cytosol. Furthermore, the results suggest that DHCB-induced Bcap37 apoptosis through mitochondria-mediated caspase-dependent pathway.
Through the experiments, we can conclude that ANDRO has been shown to suppress the growth of HCC cells and trigger apoptosis in vitro. Most important, ANDRO potentiates the cytotoxic effect of 5-FU in HCC cell line SMMC-7721 through apoptosis. The addition of ANDRO to 5-FU induces synergistic apoptosis, which could be corroborated to the increased caspase-8, p53 activity and the significant changes of Bax conformation in these cells, resulting in increased losses of mitochondrial membrane potential, increased release of cytochrome c, and activation of caspase-9 and caspase-3. The results suggest that ANDRO may be effective in combination with 5-FU for the treatment of HCC cells.
To investigate the anti-resistant ability and its molecular mechanisms of the UA, we used multidrug resistant human hepatoma cell line (R-HepG2) as a test model. The results demonstrated that the UA could inhibit the proliferation of multidrug resistant human hepatoma R-HepG2 cells through apoptosis. Furthermore, The death of R-HepG2 cells induced by UA was mainly through the caspase-independent AIF signaling pathway with the participation of Bak. And we also showed that UA was effective against R-HepG2 cells in animal study with negligible body weight loss and damage towards the liver, heart and spleen. Most importantly, immunohistochemical staining in animal tissues also suggested that UA significantly inhibited the growth of R-HepG2 cells in nude mice was also through the AIF signaling pathway.
引文
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