抗鼻咽癌中草药的筛选和盐酸千金藤碱对鼻咽癌细胞生长的影响及其机制的初步探讨
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摘要
研究背景及目的:
鼻咽癌主要发生在我国南方沿海地区,是严重影响我国人民群众身体健康的恶性肿瘤之一。目前治疗鼻咽癌的主要手段为放射治疗,5年生存率较低;化学治疗在鼻咽癌病人尤其晚期病例仍占有重要地位,但其毒副作用大,往往影响疗程的完成。中草药药效温和,毒副作用小,具有合成药物不可替代的特点。我国的传统医学在采用天然药物治疗肿瘤方面有丰富的临床经验。虽然广西中草药资源丰富,又是鼻咽癌的高发区,但针对鼻咽癌防治应用的药物研究尚为空白,有许多抗鼻咽癌活性成分和方剂急待筛选开发应用。因此,通过药物筛选寻找针对鼻咽癌更有效、毒副反应更少的中草药是临床治疗迫切需要解决的问题之一。
课题组通过两种途径对中草药的抗鼻咽癌作用进行初步筛选:一、采用血清药理学方法制备中草药的含药血清,在体外用MTT法对含药血清的抗鼻咽癌作用进行筛选;二、在体外用MTT法直接对中草药的提取物进行抗鼻咽癌作用的筛选。筛选实验显示半枝莲、肿节风等的含药血清和茶多酚、薏苡仁的提取物在体外可以有效抑制鼻咽癌细胞的生长。签于资料显示青蒿、千金藤在抗肿瘤方面的作用,本实验在课题组工作的基础上分别通过同样的两种途径对青蒿含药血清和千金藤的提取物(盐酸千金藤碱)在体外用MTT法进行了抗鼻咽癌作用的初步筛选,并对盐酸千金藤碱对鼻咽癌癌细胞生长的抑制作用及其作用机制进行了探讨。
材料与方法:
(1)采用MTT法检测盐酸千金藤碱和含青蒿血清在体外鼻对咽癌细胞CNE-1、CNE-2、5-8F、SUNE-1的生长抑制作用,筛选抗鼻咽癌中草药;
(2)盐酸千金藤碱处理的人鼻咽癌CNE-1、CNE-2、5-8F、SUNE-1细胞株后,采用ATP法对其进行细胞活力测定、流式细胞术分析其细胞周期及透射电镜观察其细胞形态;
(3)采用基因芯片技术检测盐酸千金藤碱处理前后CNE-2细胞的基因表达谱改变;用实时荧光定量PCR对部分基因芯片结果进行验证;
(4)实验数据用SPSS13.0统计软件进行分析处理。
结果:
(1)MTT法发现青蒿对CNE-1、5-8F、SUNE-1、CNE-2细胞的抑制作用不明显;盐酸千金藤碱对四株鼻咽癌细胞的抑制作用较明显,并且在CNE-1、5-8F、SUNE-1且呈剂量-效应关系和时间-效应关系,在CNE-2成剂量-效应关系;
(2)ATP法发现盐酸千金藤碱对四株鼻咽癌细胞生长有抑制作用,其效应关系同MTT结果;流式细胞仪检测发现盐酸千金藤碱处理四株鼻咽癌细胞后细胞周期停滞于G_0/G_1期,并可见凋亡峰;透射电镜可见四株鼻咽癌细胞出现细胞凋亡形态学改变;
(3)基因芯片检测得到138个上调基因和63个下调基因。依据其生物学功能可以分为细胞增殖相关基因、细胞周期相关基因、细胞凋亡相关的基因、DNA修复基因等。采用实时荧光定量PCR对部分基因进行验证,结果与基因芯片结果相符。
结论:
(1)盐酸千金藤碱(千金藤的提取物)在体外可以有效的抑制鼻咽癌细胞的生长;青蒿在体外对鼻咽癌细胞的生长没有明显的影响;
(2)盐酸千金藤碱在体外将CNE-1、CNE-2、5-8F、SUNE-1细胞阻滞于G_0/G_1期,使细胞增殖受到抑制;
(3)盐酸千金藤碱在体外可诱导CNE-1、CNE-2、5-8F、SUNE-1凋亡,可有效抑制其生长;
(4)盐酸千金藤碱可以诱导CNE-2细胞201(138个上调,63个下调)基因的差异表达。
(5)参与盐酸千金藤碱对CNE-2细胞生长的影响的基因主要有细胞增殖相关基因、细胞周期相关基因、细胞凋亡相关的基因、DNA修复基因等。推测盐酸千金藤碱对CNE-2的抑制可能是多种基因共同作用的结果。
Background and Objective:
Nasopharyngeal carcinoma(NPC),which is threating people's health seriously,is one of the most common malignant tumors in Southern China.The radiation therapy play an important role in early stage of NPC patients,but the five years survival rate is lower.Chemotherapy has the deep significance for late stage of NPC patients,but Chemotherapy often can't be finished because of its serious side effects.Our traditional medicines have the rich experiences in tumors therapy with naturally occurring drugs.The drug action of Chinese herbal medicine,which the side effect is negligible,is mild.However,the synthetic drug has not these features.It is a stringent question to find a kind of Chinese herbal medicine which have more efficient and less side effect on anti-NPC through drug screening.The project group had screened anti-NPC Chinese herbal medicine through two methods.One method is applying blood-serum pharmacology to prepare drug serum and screening them in vitro by MTT.The other method is screening the extractive of Chinese herbal medicines in vitro by MTT.At result,we found scutellariae barbatae serum、Sarcandra serum and the extractive of tea polyphenol、Semen coicis can inhibit the growth of nasopharyngeal carcinoma cells.However,the anti-NPC effect of Sweet Wormwood Herb and Cepharanthine Hydrochiorid(the extractive of Stephania japonica) have been not reported.So our project screen the two Chinese herbal medicines on anti-NPC effect in the same methods as that of the project group,and study on the actions and its mechnism of the Cepharanthine Hydrochiorid(CH) on human nasopharyngeal carcinoma cell lines.
Material and Methods:
(1) MTT assay had been used to evaluate the growth inhibition of the human nasopharyngeal carcinoma cell line—SUNE-1、CNE-1、CNE-2、5-8F treated with CH and Sweet Wormwood Herb serum,in order to find Chinese herbal medicines whether can inhibit the growth of human nasopharyngeal carcinoma cells;
(2) In the human nasopharyngeal carcinoma cell line—SUNE-1、CNE-1、CNE-2、5-8F treated with CH,we used the ATP method to test the vigor,used the flow cytometry to analysis the cell cycle and used the electron microscopes electrophores to observe morphology;
(3) DNA microarray had been used to search the different-expressed genes of human nasopharyngeal carcinoma cell CNE-2 before and after treated with CH;And some of different-expressed genes were confirmed by real time-PCR;
(4) All experimental data were analyzed with SPSS13.0 for window.
RESULTS:
(1) MTT results showed that the growth of human nasopharyngeal carcinoma cell line—SUNE-1、CNE-1、CNE-2、5-8F were not obviously inhibited by Sweet Wormwood Herb.The CH could inhibit the growth of human nasopharyngeal carcinoma cell line—SUNE-1、CNE-1、CNE-2、5-8F in vitro conspicuously.There were obviously dosage-effect and time-effect correlation in SUNE-1、CNE-1、5-8F cells,but there was only dosage-effect in CNE-2 cell;
(2) ATP method,which results were coherent with the results of MTT, showed CH could inhibit the vigor of four human nasopharyngeal carcinoma cell lines;flow cytometry analysis founded that G_1 arrest and apoptosis peak occurred in the four human nasopharyngeal carcinoma cells treated with CH; Morphological apoptosis of the four human nasopharyngeal carcinoma cells could be observed by means of electron microscope;
(3) There were 16450 Unigene tested by DNA microarray in all.There were 138 up-regulated genes and 63 down-regulated genes.According to their biological function,these genes can be classed the genes related to cell proliferation,the genes related to cell apoptosis,DNA repair genes and so on. Parts of genes were confirmed by real time-PCR and the results were corresponded to that of DNA microarray.
CONCLUSIONS:
(1) The growth of human nasopharyngeal carcinoma cell lines were not inhibited by Sweet Wormwood Herb,but CH could inhibit the proliferation of human nasopharyngeal carcinoma cell lines;
(2) CH could arrest the cell cycle of CNE-1、CNE-2、5-8F、SUNE1 at G_1 and inhibite cell proliferation.
(3) CH could induce apoptosis of CNE-1、CNE-2、5-8F、SUNE1.impact the growth of the human nasopharyngeal carcinoma cell line-SUNE-1、CNE-1、CNE-2、5-8F obviously and arrest cell cycle in G_0/G_1 and induce apoptosis in vitro;
(4)CH can induce the defferent expression of 201genes(138 up-regulated genes and 63 down-regulated genes).
(5)The genes which relate to the impact on CNE-2 growth treated with CH can be classed to:the genes relate to cell proliferation,the genes relate to cell cycle,the genes relate to cell apoptosis,DNA repair genes,and so on.we surppose that the molecular mechanism of CH on the inhibition CNE-2 cells growth may be relate to multigenes action.
鼻咽癌主要发生在我国南方沿海地区,是严重影响我国人民群众身体健康的恶性肿瘤之一。目前治疗鼻咽癌的主要手段为放射治疗,5年生存率较低;化学治疗在鼻咽癌病人尤其晚期病例仍占有重要地位,但其毒副作用大,往往影响疗程的完成。中草药药效温和,毒副作用小,具有合成药物不可替代的特点。我国的传统医学在采用天然药物治疗肿瘤方面有丰富的临床经验。虽然广西中草药资源丰富,又是鼻咽癌的高发区,但针对鼻咽癌防治应用的药物研究尚为空白,有许多抗鼻咽癌活性成分和方剂急待筛选开发应用。因此,通过药物筛选寻找针对鼻咽癌更有效、毒副反应更少的中草药是临床治疗迫切需要解决的问题之一。
课题组通过两种途径对中草药的抗鼻咽癌作用进行初步筛选:一、采用血清药理学方法制备中草药的含药血清,在体外用MTT法对含药血清的抗鼻咽癌作用进行筛选;二、在体外用MTT法直接对中草药的提取物进行抗鼻咽癌作用的筛选。筛选实验显示半枝莲、肿节风等的含药血清和茶多酚、薏苡仁的提取物在体外可以有效抑制鼻咽癌细胞的生长。签于资料显示青蒿、千金藤在抗肿瘤方面的作用,本实验在课题组工作的基础上分别通过同样的两种途径对青蒿含药血清和千金藤的提取物(盐酸千金藤碱)在体外用MTT法进行了抗鼻咽癌作用的初步筛选,并对盐酸千金藤碱对鼻咽癌癌细胞生长的抑制作用及其作用机制进行了探讨。
材料与方法:
(1)采用MTT法检测盐酸千金藤碱和含青蒿血清在体外鼻对咽癌细胞CNE-1、CNE-2、5-8F、SUNE-1的生长抑制作用,筛选抗鼻咽癌中草药;
(2)盐酸千金藤碱处理的人鼻咽癌CNE-1、CNE-2、5-8F、SUNE-1细胞株后,采用ATP法对其进行细胞活力测定、流式细胞术分析其细胞周期及透射电镜观察其细胞形态;
(3)采用基因芯片技术检测盐酸千金藤碱处理前后CNE-2细胞的基因表达谱改变;用实时荧光定量PCR对部分基因芯片结果进行验证;
(4)实验数据用SPSS13.0统计软件进行分析处理。
结果:
(1)MTT法发现青蒿对CNE-1、5-8F、SUNE-1、CNE-2细胞的抑制作用不明显;盐酸千金藤碱对四株鼻咽癌细胞的抑制作用较明显,并且在CNE-1、5-8F、SUNE-1且呈剂量-效应关系和时间-效应关系,在CNE-2成剂量-效应关系;
(2)ATP法发现盐酸千金藤碱对四株鼻咽癌细胞生长有抑制作用,其效应关系同MTT结果;流式细胞仪检测发现盐酸千金藤碱处理四株鼻咽癌细胞后细胞周期停滞于G_0/G_1期,并可见凋亡峰;透射电镜可见四株鼻咽癌细胞出现细胞凋亡形态学改变;
(3)基因芯片检测得到138个上调基因和63个下调基因。依据其生物学功能可以分为细胞增殖相关基因、细胞周期相关基因、细胞凋亡相关的基因、DNA修复基因等。采用实时荧光定量PCR对部分基因进行验证,结果与基因芯片结果相符。
结论:
(1)盐酸千金藤碱(千金藤的提取物)在体外可以有效的抑制鼻咽癌细胞的生长;青蒿在体外对鼻咽癌细胞的生长没有明显的影响;
(2)盐酸千金藤碱在体外将CNE-1、CNE-2、5-8F、SUNE-1细胞阻滞于G_0/G_1期,使细胞增殖受到抑制;
(3)盐酸千金藤碱在体外可诱导CNE-1、CNE-2、5-8F、SUNE-1凋亡,可有效抑制其生长;
(4)盐酸千金藤碱可以诱导CNE-2细胞201(138个上调,63个下调)基因的差异表达。
(5)参与盐酸千金藤碱对CNE-2细胞生长的影响的基因主要有细胞增殖相关基因、细胞周期相关基因、细胞凋亡相关的基因、DNA修复基因等。推测盐酸千金藤碱对CNE-2的抑制可能是多种基因共同作用的结果。
Background and Objective:
Nasopharyngeal carcinoma(NPC),which is threating people's health seriously,is one of the most common malignant tumors in Southern China.The radiation therapy play an important role in early stage of NPC patients,but the five years survival rate is lower.Chemotherapy has the deep significance for late stage of NPC patients,but Chemotherapy often can't be finished because of its serious side effects.Our traditional medicines have the rich experiences in tumors therapy with naturally occurring drugs.The drug action of Chinese herbal medicine,which the side effect is negligible,is mild.However,the synthetic drug has not these features.It is a stringent question to find a kind of Chinese herbal medicine which have more efficient and less side effect on anti-NPC through drug screening.The project group had screened anti-NPC Chinese herbal medicine through two methods.One method is applying blood-serum pharmacology to prepare drug serum and screening them in vitro by MTT.The other method is screening the extractive of Chinese herbal medicines in vitro by MTT.At result,we found scutellariae barbatae serum、Sarcandra serum and the extractive of tea polyphenol、Semen coicis can inhibit the growth of nasopharyngeal carcinoma cells.However,the anti-NPC effect of Sweet Wormwood Herb and Cepharanthine Hydrochiorid(the extractive of Stephania japonica) have been not reported.So our project screen the two Chinese herbal medicines on anti-NPC effect in the same methods as that of the project group,and study on the actions and its mechnism of the Cepharanthine Hydrochiorid(CH) on human nasopharyngeal carcinoma cell lines.
Material and Methods:
(1) MTT assay had been used to evaluate the growth inhibition of the human nasopharyngeal carcinoma cell line—SUNE-1、CNE-1、CNE-2、5-8F treated with CH and Sweet Wormwood Herb serum,in order to find Chinese herbal medicines whether can inhibit the growth of human nasopharyngeal carcinoma cells;
(2) In the human nasopharyngeal carcinoma cell line—SUNE-1、CNE-1、CNE-2、5-8F treated with CH,we used the ATP method to test the vigor,used the flow cytometry to analysis the cell cycle and used the electron microscopes electrophores to observe morphology;
(3) DNA microarray had been used to search the different-expressed genes of human nasopharyngeal carcinoma cell CNE-2 before and after treated with CH;And some of different-expressed genes were confirmed by real time-PCR;
(4) All experimental data were analyzed with SPSS13.0 for window.
RESULTS:
(1) MTT results showed that the growth of human nasopharyngeal carcinoma cell line—SUNE-1、CNE-1、CNE-2、5-8F were not obviously inhibited by Sweet Wormwood Herb.The CH could inhibit the growth of human nasopharyngeal carcinoma cell line—SUNE-1、CNE-1、CNE-2、5-8F in vitro conspicuously.There were obviously dosage-effect and time-effect correlation in SUNE-1、CNE-1、5-8F cells,but there was only dosage-effect in CNE-2 cell;
(2) ATP method,which results were coherent with the results of MTT, showed CH could inhibit the vigor of four human nasopharyngeal carcinoma cell lines;flow cytometry analysis founded that G_1 arrest and apoptosis peak occurred in the four human nasopharyngeal carcinoma cells treated with CH; Morphological apoptosis of the four human nasopharyngeal carcinoma cells could be observed by means of electron microscope;
(3) There were 16450 Unigene tested by DNA microarray in all.There were 138 up-regulated genes and 63 down-regulated genes.According to their biological function,these genes can be classed the genes related to cell proliferation,the genes related to cell apoptosis,DNA repair genes and so on. Parts of genes were confirmed by real time-PCR and the results were corresponded to that of DNA microarray.
CONCLUSIONS:
(1) The growth of human nasopharyngeal carcinoma cell lines were not inhibited by Sweet Wormwood Herb,but CH could inhibit the proliferation of human nasopharyngeal carcinoma cell lines;
(2) CH could arrest the cell cycle of CNE-1、CNE-2、5-8F、SUNE1 at G_1 and inhibite cell proliferation.
(3) CH could induce apoptosis of CNE-1、CNE-2、5-8F、SUNE1.impact the growth of the human nasopharyngeal carcinoma cell line-SUNE-1、CNE-1、CNE-2、5-8F obviously and arrest cell cycle in G_0/G_1 and induce apoptosis in vitro;
(4)CH can induce the defferent expression of 201genes(138 up-regulated genes and 63 down-regulated genes).
(5)The genes which relate to the impact on CNE-2 growth treated with CH can be classed to:the genes relate to cell proliferation,the genes relate to cell cycle,the genes relate to cell apoptosis,DNA repair genes,and so on.we surppose that the molecular mechanism of CH on the inhibition CNE-2 cells growth may be relate to multigenes action.
引文
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