异硫代氰酸酯抗癌活性及MTBITC诱导A549细凋亡机理的研究
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摘要
近年来,肺癌的发病率和死亡率在世界范围内呈不断上升趋势,其中80%-85%表现为非小细胞肺癌。流行病学研究表明,十字花科蔬菜的摄入可降低癌症的患病率,其最有效成分为硫代葡萄糖苷(简称硫苷)的降解产物—异硫代氰酸酯(ITCs)。目前,对十字花科蔬菜中ITCs的研究主要集中在组分分析及含量的测定,而对其单体的分离研究较少；ITCs的结构与活性之间的关系尚不明确；其诱导肿瘤凋亡机制尚未见详尽报道。莱菔素(MTBITC)诱导人非小细胞肺癌A549细胞凋亡的信号转导途径及作用机理的研究尚未见报道。
本论文以分离得到的5个ITCs为研究对象,对其体外抗肿瘤活性进行了药效学评价,并从量子化学角度分析了其结构与活性的关系。并以人非小细胞肺癌A549细胞为靶细胞,研究了MTBITC诱导A549细胞凋亡的机理。主要研究结论如下：
1、为优化硫苷的酶解条件,以一点红萝卜种子为研究对象,MTBITC得率为指标,采用响应面法优化确定最佳酶解条件为：酶解温度25℃,酶解时间8 h,Vc添加量0.06 mg/g,酶解pH值为3.71。MTBITC的实际得率为3.53 mg/g。
2、采用丙酮提取,利用多种现代色谱技术(硅胶柱层析,Sephadex LH-20凝胶色谱,高效液相制备等)从一点红萝卜、澄海粗条芥蓝、牛心甘蓝、西兰花种子中分离得到了5个ITCs,分别鉴定为莱菔素(MTBITC) (Ⅰ)、3-(甲硫基)丙基异硫代氰酸酯(Iberverin) (Ⅱ)、萝卜硫素(Sulforaphane) (Ⅲ)、3-(甲磺酰基)丙基异硫代氰酸酯(Iberin) (Ⅳ)和3-丁烯基异硫代氰酸酯(3-BITC) (Ⅴ)。
3、对5个ITCs体外抗肿瘤活性的药效学评价表明,MTBITC. Sulforaphane和Iberin对人肺癌A549和LAC、人肝癌HepG2、人宫颈癌HELA细胞均有明显的抑制作用。A549细胞对MTBITC的敏感性最强；MTBITC, Sulforaphane和Iberin对HepG2、LAC和HELA细胞的抑制作用相似,但明显强于Iberverin和3-BITC。
4、基于DMol3模块,从量子化学角度对5个ITCs进行几何构型优化,在此结构基础上进行Mulliken电荷分布及前线轨道能量计算,分析了ITCs的活性位点,及其抗癌活性与电子结构的关系。结果表明,ITCs的特征基团N=C=S中间C原子作为亲电位点,侧链上的磺酰基和硫基为辅助位点,使其具有一定的抗癌活性。ITCs的抗癌活性差异与ITCs分子的负电荷分布、前线分子轨道的离域性及最低未占据轨道能量和最高占据轨道能量的差值(△EL-H)有关。
5、MTBITC以剂量—时间依赖性抑制A549细胞增殖,其抑制肿瘤细胞增殖主要通过诱导细胞凋亡,而非坏死。形态学研究,发现MTBITC使A549细胞出现典型的凋亡形态；PI单染和AnnexinV/PI双染流式细胞术分析,表明A549细胞经MTBITC处理后出现明显的凋亡峰,细胞周期阻滞于S期和G2／M期,细胞以早期凋亡为主,呈剂量依赖性。分子对接研究表明,MTBITC与微管蛋白疏水区域内部的Cys347残基以共价键结合,与Lys352残基以氢键结合,说明MTBITC通过影响微管蛋白的价键,阻滞细胞周期,诱导细胞凋亡。
6、采用RT-PCR法、流式细胞术、Caspase分光光度检测法等,分析凋亡过程中相关基因1mRNA表达情况,检测线粒体膜电位(△ψm)、活性氧(ROS)、Ca2+浓度及Caspase-3、-8、-9的变化,探讨MTBITC诱导A549细胞凋亡的机理。结果显示,MTBITC使△Ψm降低,细胞内游离的ROS和Ca2+浓度含量升高,Bc1-2、Bcl-xL的mRNA表达下调,Bax和Bid mRNA表达上调,Caspase-9被激活,且具有时间依赖性,说明线粒体途径和Bcl-2基因家族参与了MTBITC诱导A549细胞凋亡的调控。同时,MTBITC使细胞Fas、FADD mRNA表达增强,Caspase-8,-3活性升高,且具有时间依赖性,表明MTBITC通过Fas途径引起A549细胞凋亡。
结果证明,MTBITC通过改变微管蛋白的价键,从而阻滞细胞的周期,并通过线粒体和Fas受体信号通路,进而激活Caspase级联反应诱导A549细胞凋亡。该凋亡效应也与钙离子相关的活性氧信号通路有关。本论文的研究结果为深度开发十字花科植物资源提供了科学依据,为ITCs治疗肺癌类疾病提供了基础研究数据。
The morbidity and mortality of lung cancer show an upward trend in recent years. Epidemiological studies reveal that high dietary intake of cruciferous vegetables containing isothiocyanates (ITCs) can lower the risk from cancers. A lot of literatures reported the composition and content of ITCs in cruciferous vegetables, but few involved the preparative separation of ITCs, which are the material foundation of bioactive studies. Anticancer activity of more than 20 ITCs was studied, but structure-activity relationship of ITCS has not been clarified. Also the studied of mechanism of ITCs-induced apoptosis and the signal transduction have not been reported. The present dissertation focuses on the isolation and identification of five ITCs from four cruciferous vegetables, the effects of ITCs on human cancer cells, the structure-activity relationship of ITCs, and the effects of MTBITC (4-(methylthio)-3-butenyl isothiocyanate) on the signal transduction pathways in A549 cells apoptosis. The main results are listed as follows:
1. The hydrolyzation of glucosinolate to obtain ITCs from dried radish seeds was optimized as following:temperature,25℃; time,8 hours; quantity of activator,0.06 mg/g and pH,3.71. The yield rate of MTBITC under the above hydrolyzation condition was 3.53 mg/g.
2. The acetone extracts of hydrolysates of four cruciferous vegetables seeds were extracted and separated by chromatographic methods on silica gel, Sephadex LH-20 and Pre-HPLC to yield 5 compounds:MTBITC (Ⅰ), Iberverin (Ⅱ), Sulforaphane (Ⅲ), Iberin (Ⅳ) and 3-BITC(Ⅴ).
3. The inhibition activity of five ITCs agaist human cancer cells A549, LAC, HepG2 and HELA were tested. The results demonstrated that MTBITC, Sulforaphane and Iberin could significantly inhibit the growth of the four human cancer cell lines in a dose-manner, the cell growth inhibition rates of MTBITC, Sulforaphane and Iberin were higher than Iberverin and 3-BITC, and the inhibitory activity of MTBITC to A549 was the strongest.
4. The relationship between the electronic structure and anticancer activity was analyzed with the parameters of the geometry, Mulliken populations and the atomic frontier electron densities which were optimized by DMol3 module. The results showed that carbon atom in the group of N=C=S of the ITCs is the main electrophonic reaction site, and sulfonyl or sulfur in the side chain was the secondary site. The analysis also clued that the anticancer activities of ITCs was relative to the negative charge populations, delocalization of frontier molecular orbital and the energy gaps of HOMO-LUMO.
5. Effects of MTBITC on A549 cells were investigated by MTT method. The results showed that MTBITC suppressed the growth of A549 cells in-vitro with both dose-and time-dependant manners, and the inhibition of MTBITC on A549 cell proliferation belong to the apoptosis induction, not necrosis. Conventional morphological signs of apoptosis could be found when the cells were treated with MTBITC, through the methods including Giemsa stain, Hoechst 33258 fluorescence stain and transmission electron microscope. MTBITC treatment significantly increased the apoptotic sub-Gl fraction in dose-dependent manner by PI staining. The result of flow cytometry (FCM) exhibited induced apoptosis was blocked at phases of S and G2/M, and MTBITC-induced cell apoptosis is mainly at the earlier stage of apoptosis. On the basis of Molecular docking, we found that MTBITC covaiently interacted with the Cys347 residue and formed hydrogen bonds with Lys352 in the lipophilic pockets, which disrupted the tubulin polymerization and induced the cancer cells apoptosis.
6. The mechanism of apoptosis induced by MTBITC was investigated by testing the change of mitochondrial membrane potential (△(?)m), reactive oxygen species (ROS) and intracellular calcium with FCM, the expression of mRNA of apoptosis-related gene by RT-PCR, and the activities of Caspase-3,-8,-9 by caspase colorimetric assay. The results indicated that MTBITC treatment decreased mitochondrial membrane potential by down-regulating the rate of Bcl-2/Bax and Bcl-xL/Bax, increased ROS and intracellular calcium and activated Caspase-9. Therefore, mitochondrial pathway and Bcl-2 gene family could involve in the mechanism of the A549 cells apoptosis induced by MTBITC. Further investigation indicated that the mRNA expression of Fas, FasL and FADD were up-regulated in a time-dependent manner, Caspase-3 and-8 were activated. These results demonstrated that MTBITC induced apoptosis of A549 cells via Fas signal transduction pathway.
All the above results indicated the apoptosis of A549 cells was induced by MTBITC by changing the valencebonds of tubulin to block cells entering S and G2/M phases via Fas signal transduction pathway and mitochondria pathway. And the mechanism of A549 cells apoptosis induced by MTBITC should be relative to the calcium-dependent ROS pathway. Those results will provide scientific information for developing healthcare products using cruciferous vegetables or developing medicines for cancer treatment.
本论文以分离得到的5个ITCs为研究对象,对其体外抗肿瘤活性进行了药效学评价,并从量子化学角度分析了其结构与活性的关系。并以人非小细胞肺癌A549细胞为靶细胞,研究了MTBITC诱导A549细胞凋亡的机理。主要研究结论如下：
1、为优化硫苷的酶解条件,以一点红萝卜种子为研究对象,MTBITC得率为指标,采用响应面法优化确定最佳酶解条件为：酶解温度25℃,酶解时间8 h,Vc添加量0.06 mg/g,酶解pH值为3.71。MTBITC的实际得率为3.53 mg/g。
2、采用丙酮提取,利用多种现代色谱技术(硅胶柱层析,Sephadex LH-20凝胶色谱,高效液相制备等)从一点红萝卜、澄海粗条芥蓝、牛心甘蓝、西兰花种子中分离得到了5个ITCs,分别鉴定为莱菔素(MTBITC) (Ⅰ)、3-(甲硫基)丙基异硫代氰酸酯(Iberverin) (Ⅱ)、萝卜硫素(Sulforaphane) (Ⅲ)、3-(甲磺酰基)丙基异硫代氰酸酯(Iberin) (Ⅳ)和3-丁烯基异硫代氰酸酯(3-BITC) (Ⅴ)。
3、对5个ITCs体外抗肿瘤活性的药效学评价表明,MTBITC. Sulforaphane和Iberin对人肺癌A549和LAC、人肝癌HepG2、人宫颈癌HELA细胞均有明显的抑制作用。A549细胞对MTBITC的敏感性最强；MTBITC, Sulforaphane和Iberin对HepG2、LAC和HELA细胞的抑制作用相似,但明显强于Iberverin和3-BITC。
4、基于DMol3模块,从量子化学角度对5个ITCs进行几何构型优化,在此结构基础上进行Mulliken电荷分布及前线轨道能量计算,分析了ITCs的活性位点,及其抗癌活性与电子结构的关系。结果表明,ITCs的特征基团N=C=S中间C原子作为亲电位点,侧链上的磺酰基和硫基为辅助位点,使其具有一定的抗癌活性。ITCs的抗癌活性差异与ITCs分子的负电荷分布、前线分子轨道的离域性及最低未占据轨道能量和最高占据轨道能量的差值(△EL-H)有关。
5、MTBITC以剂量—时间依赖性抑制A549细胞增殖,其抑制肿瘤细胞增殖主要通过诱导细胞凋亡,而非坏死。形态学研究,发现MTBITC使A549细胞出现典型的凋亡形态；PI单染和AnnexinV/PI双染流式细胞术分析,表明A549细胞经MTBITC处理后出现明显的凋亡峰,细胞周期阻滞于S期和G2／M期,细胞以早期凋亡为主,呈剂量依赖性。分子对接研究表明,MTBITC与微管蛋白疏水区域内部的Cys347残基以共价键结合,与Lys352残基以氢键结合,说明MTBITC通过影响微管蛋白的价键,阻滞细胞周期,诱导细胞凋亡。
6、采用RT-PCR法、流式细胞术、Caspase分光光度检测法等,分析凋亡过程中相关基因1mRNA表达情况,检测线粒体膜电位(△ψm)、活性氧(ROS)、Ca2+浓度及Caspase-3、-8、-9的变化,探讨MTBITC诱导A549细胞凋亡的机理。结果显示,MTBITC使△Ψm降低,细胞内游离的ROS和Ca2+浓度含量升高,Bc1-2、Bcl-xL的mRNA表达下调,Bax和Bid mRNA表达上调,Caspase-9被激活,且具有时间依赖性,说明线粒体途径和Bcl-2基因家族参与了MTBITC诱导A549细胞凋亡的调控。同时,MTBITC使细胞Fas、FADD mRNA表达增强,Caspase-8,-3活性升高,且具有时间依赖性,表明MTBITC通过Fas途径引起A549细胞凋亡。
结果证明,MTBITC通过改变微管蛋白的价键,从而阻滞细胞的周期,并通过线粒体和Fas受体信号通路,进而激活Caspase级联反应诱导A549细胞凋亡。该凋亡效应也与钙离子相关的活性氧信号通路有关。本论文的研究结果为深度开发十字花科植物资源提供了科学依据,为ITCs治疗肺癌类疾病提供了基础研究数据。
The morbidity and mortality of lung cancer show an upward trend in recent years. Epidemiological studies reveal that high dietary intake of cruciferous vegetables containing isothiocyanates (ITCs) can lower the risk from cancers. A lot of literatures reported the composition and content of ITCs in cruciferous vegetables, but few involved the preparative separation of ITCs, which are the material foundation of bioactive studies. Anticancer activity of more than 20 ITCs was studied, but structure-activity relationship of ITCS has not been clarified. Also the studied of mechanism of ITCs-induced apoptosis and the signal transduction have not been reported. The present dissertation focuses on the isolation and identification of five ITCs from four cruciferous vegetables, the effects of ITCs on human cancer cells, the structure-activity relationship of ITCs, and the effects of MTBITC (4-(methylthio)-3-butenyl isothiocyanate) on the signal transduction pathways in A549 cells apoptosis. The main results are listed as follows:
1. The hydrolyzation of glucosinolate to obtain ITCs from dried radish seeds was optimized as following:temperature,25℃; time,8 hours; quantity of activator,0.06 mg/g and pH,3.71. The yield rate of MTBITC under the above hydrolyzation condition was 3.53 mg/g.
2. The acetone extracts of hydrolysates of four cruciferous vegetables seeds were extracted and separated by chromatographic methods on silica gel, Sephadex LH-20 and Pre-HPLC to yield 5 compounds:MTBITC (Ⅰ), Iberverin (Ⅱ), Sulforaphane (Ⅲ), Iberin (Ⅳ) and 3-BITC(Ⅴ).
3. The inhibition activity of five ITCs agaist human cancer cells A549, LAC, HepG2 and HELA were tested. The results demonstrated that MTBITC, Sulforaphane and Iberin could significantly inhibit the growth of the four human cancer cell lines in a dose-manner, the cell growth inhibition rates of MTBITC, Sulforaphane and Iberin were higher than Iberverin and 3-BITC, and the inhibitory activity of MTBITC to A549 was the strongest.
4. The relationship between the electronic structure and anticancer activity was analyzed with the parameters of the geometry, Mulliken populations and the atomic frontier electron densities which were optimized by DMol3 module. The results showed that carbon atom in the group of N=C=S of the ITCs is the main electrophonic reaction site, and sulfonyl or sulfur in the side chain was the secondary site. The analysis also clued that the anticancer activities of ITCs was relative to the negative charge populations, delocalization of frontier molecular orbital and the energy gaps of HOMO-LUMO.
5. Effects of MTBITC on A549 cells were investigated by MTT method. The results showed that MTBITC suppressed the growth of A549 cells in-vitro with both dose-and time-dependant manners, and the inhibition of MTBITC on A549 cell proliferation belong to the apoptosis induction, not necrosis. Conventional morphological signs of apoptosis could be found when the cells were treated with MTBITC, through the methods including Giemsa stain, Hoechst 33258 fluorescence stain and transmission electron microscope. MTBITC treatment significantly increased the apoptotic sub-Gl fraction in dose-dependent manner by PI staining. The result of flow cytometry (FCM) exhibited induced apoptosis was blocked at phases of S and G2/M, and MTBITC-induced cell apoptosis is mainly at the earlier stage of apoptosis. On the basis of Molecular docking, we found that MTBITC covaiently interacted with the Cys347 residue and formed hydrogen bonds with Lys352 in the lipophilic pockets, which disrupted the tubulin polymerization and induced the cancer cells apoptosis.
6. The mechanism of apoptosis induced by MTBITC was investigated by testing the change of mitochondrial membrane potential (△(?)m), reactive oxygen species (ROS) and intracellular calcium with FCM, the expression of mRNA of apoptosis-related gene by RT-PCR, and the activities of Caspase-3,-8,-9 by caspase colorimetric assay. The results indicated that MTBITC treatment decreased mitochondrial membrane potential by down-regulating the rate of Bcl-2/Bax and Bcl-xL/Bax, increased ROS and intracellular calcium and activated Caspase-9. Therefore, mitochondrial pathway and Bcl-2 gene family could involve in the mechanism of the A549 cells apoptosis induced by MTBITC. Further investigation indicated that the mRNA expression of Fas, FasL and FADD were up-regulated in a time-dependent manner, Caspase-3 and-8 were activated. These results demonstrated that MTBITC induced apoptosis of A549 cells via Fas signal transduction pathway.
All the above results indicated the apoptosis of A549 cells was induced by MTBITC by changing the valencebonds of tubulin to block cells entering S and G2/M phases via Fas signal transduction pathway and mitochondria pathway. And the mechanism of A549 cells apoptosis induced by MTBITC should be relative to the calcium-dependent ROS pathway. Those results will provide scientific information for developing healthcare products using cruciferous vegetables or developing medicines for cancer treatment.
引文
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