冬凌草甲素抗乳腺癌作用及机理研究
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摘要
细胞周期(cell cycle)是指连续分裂的细胞从上一次分裂结束开始到下一次分裂结束为止的细胞生命活动的基本过程,分为间期(G1期、S期和G2期)和分裂期(M期)两个阶段。细胞周期的动态平衡是多细胞生物体维持自身稳定的重要因素,由细胞增殖、生长阻滞和细胞凋亡共同调节。当致癌物质存在时,基因由于发生突变、缺失、扩增、异位等变化,使动态平衡被打乱,可导致细胞周期失控,异常细胞无限增殖从而形成肿瘤,因此,肿瘤是一类细胞周期紊乱、细胞失控性生长的疾病。
细胞在长期进化过程中发展并建立了一系列调控细胞周期进程的机制,就是“细胞周期检查点(cell cycle checkpoint)机制”。包括G1/S期检验点、S期检验点和G2/M期检验点。当细胞DNA受到物理、化学或生物等各种刺激而发生损伤时,细胞便会激活此机制,暂停细胞周期的进行,为损伤的DNA提供时间,同时诱导促修复基因的转录来修复受损DNA,确保遗传信息的准确传递,待修复这些损伤后,细胞周期恢复运转。一般认为,当DNA损伤不能被有效修复时,细胞发生凋亡。
细胞凋亡(Apoptosis-APO)是由基因控制的、高度有序的细胞生理性的主动死亡过程,对维持机体内环境的稳定和生物体的生长发育有着极其重要的作用。细胞凋亡与细胞增殖一样,是生命活动的重要组成部分,二者受一系列相关基因的调控而维持一个动态的平衡,一旦此平衡被破坏,将导致机体产生疾病。研究证明,肿瘤的发生与细胞凋亡机制的紊乱密切相关,如果受损细胞的凋亡机制不能正常启动,机体内细胞增殖与凋亡的平衡将被破坏,导致细胞过度增殖,就有可能引起肿瘤的产生。
本课题体外以人乳腺癌MCF-7细胞为研究对象,探讨冬凌草甲素(Oridonin, ORI)对其细胞周期阻滞信号转导途径和细胞凋亡信号转导途径的调控,并观察ORI体内诱导乳腺癌细胞凋亡的作用。结果表明：ORI可通过ATM-p53-p21WAF1/CIP1和ATM-Chk2-Cdc25C信号途径诱导人乳腺癌MCF-7细胞G2/M期周期阻滞；ORI诱导MCF-7细胞凋亡的信号转导途径为死亡受体途径(Fas途径)和线粒体途径。体内实验表明：ORI对机体无明显毒副作用,可抑制乳腺癌移植瘤的生长；ORI在体内通过死亡受体(Fas途径)途径和线粒体途径诱发人乳腺癌裸鼠移植瘤细胞凋亡
Aim:The breast cancer, one of the most common female malignancies, poses a threat for women's health, the incident of which is the highest among all the malignancies. The treatment of breast cancer at present involves surgery, chemotherapy, radiotherapy and drug therapy. The therapeutic effect of surgery on breast cancer is not remarkable due to the low rate of the diagnosis in early phase of cancers. The toxic and adverse effects as well as immunologic injury posed by the radiotherapy and chemotherapy on the human being are serious, which limits their applications. Therefore, most researchers concentrate on screening Chinese traditional herbs which have anti-cancer effects.
Oridonin(ORI.), one of the tetracyclic diterpenoid compounds, which is extracted from the traditional Chinese herb named Rabdosia rubescens, is effective in inhibiting the growth of many malignancy cells. As a good effective traditional Chinese herb which can treat esophageal carcinoma and cardiac carcinoma, oridonin has been accepted by traditional medicine experts in China. However, there is few research have been reported that the oridonin's anti-tumor effects and potential mechanism on breast cancer, which makes clinical research of oridonin lack certain theoretical foundation and hinders widely development of the drug.
Our research is the first through the study of ORI on human breast cancer cell line MCF-7DNA injury and regulation of MCF-7cell cycle arrest and apoptosis signal transduction and ORI induced mammary carcinoma in nude mice transplanted tumor cell apoptosis. It revealed ORI resistant breast cancer action target point, studied its anti breast cancer mechanism, the clinical application of ORI treatment of breast cancer and lay the theoretical foundation.
Methods:
(A). In vitro experiments: The inhibition effect of different concentrations(10μmol/L、20μmol/L、40μmol/L、80μmol/L and160μmol/L) of ORI on MCF-7cell proliferation on different times was tested(24h、48h and72h);
The comet assay for the detection of single cell DNA damage; Immunofluorescence assay for the detection of r-h2ax, p-ATM protein expression; PI single staining and flow cytometry for cell cycle distribution; Annexin V-FITC/PI double-labeled apoptosis with flow cytometry and Western blot for detection of cell cycle arrest and apoptosis related protein expression; Transmission electron microscopic was hired for observation of cell morphology using ultrathin sections.
(B). In vivo experiments:
The mouse acute toxicity test for the detection of ORI medication safety:Human breast cancer MCF-7cells were inoculated into nude mice under the armpit,7days after transplantation tumor in nude mice will get tumors about4mm-5mm in diameter, that means transplantation was successfully established;
Giving ORI for14consecutive days and then measured the average tumor weight in the control group and the test group and calculation of the tumor inhibition rate:Dissection of each tumor tissue and making a cell morphological examination; Detection of apoptotic cells in nude mice by TUNEL test;
Double staining flow cytometry of cells apoptosis in nude mice transplanted tumor rate; Using western-blot detecting cells apoptosis in nude mice transplanted tumor associated protein expression.
Results
Resuls in vitro:
(1). The inhibition effect of different concentrations (10μmol/L、20μmol/L、40μmol/L、80μmol/L and160μmol/L) of ORI on MCF-7cell proliferation on different times (24h、48h and72h) was tested and the results showed:ORI has a direct inhibitory effect on MCF-7cells in vitro, which is in a time and dose dependent. The IC50of ORI to MCF7cells is78.3μmol/L after ORI was applied to it after48hours;
(2).The comet assay showed, at concentration of80μmol/L and160μmol/L after48h applied, ORI can induce the DNA damage of MCF-7cells and it showed a dose-effect relationship;
(3). Immunofluorescence experiments showed that ORI can induce the increase of expression of r-h2ax and p-ATM proteins of MCF7cells at concentration of80μmol/L and160μmol/L after48h applied,;
(4). Flow cytometry in cell cycle distribution showed that ORI induced MCF7stagnation in G2phase of cell cycle at concentration of10μmol/L、20μmol/L、40μmol/L、80μmol/L and160μmol/L after48h with a dose-dependent relationship;
(5). Flow cytometry apoptosis detection kit (Annexin V-FITC) showed that the ORI can induce apoptosis in MCF-7cells and the rate of apoptosis is dose-dependent at concentration of10μmol/L、20μmol/L、40μmol/L、80μmol/L and160μmol/L after72h;
(6). Western blotting protein detection showed that, at concentration of10μmol/L20μmol/L、40μmol/L、80μmol/L and160μmol/L after48h, ORI can up-regulate the protein expressions of p-ATM、r-H2AX、p-CHK2、p-Cdc2、p-Cdc25C and Cycling Bl. It prompted that ORI may induced MCF7stagnation in G2/M phase of cell cycle and then induced cell cycle arrest through ATM-p53-p21WAF1/CIP1and ATM-Chk2-Cdc25C signal pathway;
(7). Western blotting protein detection showed that, at concentration of10μmol/L20μmol/L、40μmol/L、80μmol/L and160μmol/L after72h, ORI can make down-regulation of the expression of Bcl-12protein and up-regulation of the expression of Bax、Fas and cleaved-caspase3proteins with a dose-dependently pattern and reduce the rate of Bcl-2/Bax. The above results implicated that ORI induced some special proteins expression of MCF-7cells may through the road of decease of the receptors and chondriosomes;
(8). By ultrathin sections, transmission electron microscopy showed ORI can induce a representative MCF-7cells apoptosis at concentration of80μmol/L and160μmol/L after72h.
Results in vivo experiments:
(1). The mouse acute toxicity test showed that the mouse liver and kidney either their structure or function index are within the normal stage after treatment. Results indicated that, ORI, on organism level, has no obvious side effect ant it is in a high safety of medication.
(2). We made a successful establishment of human breast carcinoma model in nude mice as the human breast cancer MCF-7cell can be vaccinated in nude mice;
(3). The tumor inhibition rates of ORI (High) group and ORI (Low) group were36.7%and34.6%specially and there is a significantly difference compared with the control group(p<0.01);
(4). Tumor cells decreased obviously after giving ORI and CTX. The tumor cells heteromorphism showed a trend from the low differentiation to moderately differentiation and a massive necrosis of tumor cells and the reversion of malignant phenotypes was found;
(5). Result of TUNEL method test showed that ORI can induce apoptosis of tumor cells in vivo;
(6). The percentage of apoptotic cells of ORI (L)、ORI (H) and CTX group are17.02±4.98%、22.37±6.43%and27.46±6.09%respectively. There are significantly differences compared ORI (H) and CTX groups with the control group (6.24+-2.32%).(p<0.05and0.01);
(7). By Annexin V-FITC/PI double-labeled apoptosis with flow cytometry test, the results showed that the percentage of apoptotic cells of ORI(L、ORI (H) and CTX group are32.60%、14.23%and26.73%respectively. There are significantly differences in apoptosis rate compared with the control group (p<0.05and p<0.01);
(8). ORI can increase the proteins expressions of cleaved Caspase-3、cleaved Caspase-8、 cleaved Caspase-9、Fas、Cyt-c and Bax in dose-dependent. ORI can induce transplant tumor cells apoptosis through the road of decease of the receptors and chondriosomes.
Conclusion:Our research demonstrates that oridonin have the effect of anti-breast cancer in vivo and vitro, the mechanism of which involves inhibiting cancer cells growth through inducing cell cycle arrest and promoting cell apoptosis by inducing the activation of the Fas signal transduction pathway and the mitochondria pathway. Oridonin has no obvious side effect and it is expected to be used in clinical treatment for breast cancer in the near future.
细胞在长期进化过程中发展并建立了一系列调控细胞周期进程的机制,就是“细胞周期检查点(cell cycle checkpoint)机制”。包括G1/S期检验点、S期检验点和G2/M期检验点。当细胞DNA受到物理、化学或生物等各种刺激而发生损伤时,细胞便会激活此机制,暂停细胞周期的进行,为损伤的DNA提供时间,同时诱导促修复基因的转录来修复受损DNA,确保遗传信息的准确传递,待修复这些损伤后,细胞周期恢复运转。一般认为,当DNA损伤不能被有效修复时,细胞发生凋亡。
细胞凋亡(Apoptosis-APO)是由基因控制的、高度有序的细胞生理性的主动死亡过程,对维持机体内环境的稳定和生物体的生长发育有着极其重要的作用。细胞凋亡与细胞增殖一样,是生命活动的重要组成部分,二者受一系列相关基因的调控而维持一个动态的平衡,一旦此平衡被破坏,将导致机体产生疾病。研究证明,肿瘤的发生与细胞凋亡机制的紊乱密切相关,如果受损细胞的凋亡机制不能正常启动,机体内细胞增殖与凋亡的平衡将被破坏,导致细胞过度增殖,就有可能引起肿瘤的产生。
本课题体外以人乳腺癌MCF-7细胞为研究对象,探讨冬凌草甲素(Oridonin, ORI)对其细胞周期阻滞信号转导途径和细胞凋亡信号转导途径的调控,并观察ORI体内诱导乳腺癌细胞凋亡的作用。结果表明：ORI可通过ATM-p53-p21WAF1/CIP1和ATM-Chk2-Cdc25C信号途径诱导人乳腺癌MCF-7细胞G2/M期周期阻滞；ORI诱导MCF-7细胞凋亡的信号转导途径为死亡受体途径(Fas途径)和线粒体途径。体内实验表明：ORI对机体无明显毒副作用,可抑制乳腺癌移植瘤的生长；ORI在体内通过死亡受体(Fas途径)途径和线粒体途径诱发人乳腺癌裸鼠移植瘤细胞凋亡
Aim:The breast cancer, one of the most common female malignancies, poses a threat for women's health, the incident of which is the highest among all the malignancies. The treatment of breast cancer at present involves surgery, chemotherapy, radiotherapy and drug therapy. The therapeutic effect of surgery on breast cancer is not remarkable due to the low rate of the diagnosis in early phase of cancers. The toxic and adverse effects as well as immunologic injury posed by the radiotherapy and chemotherapy on the human being are serious, which limits their applications. Therefore, most researchers concentrate on screening Chinese traditional herbs which have anti-cancer effects.
Oridonin(ORI.), one of the tetracyclic diterpenoid compounds, which is extracted from the traditional Chinese herb named Rabdosia rubescens, is effective in inhibiting the growth of many malignancy cells. As a good effective traditional Chinese herb which can treat esophageal carcinoma and cardiac carcinoma, oridonin has been accepted by traditional medicine experts in China. However, there is few research have been reported that the oridonin's anti-tumor effects and potential mechanism on breast cancer, which makes clinical research of oridonin lack certain theoretical foundation and hinders widely development of the drug.
Our research is the first through the study of ORI on human breast cancer cell line MCF-7DNA injury and regulation of MCF-7cell cycle arrest and apoptosis signal transduction and ORI induced mammary carcinoma in nude mice transplanted tumor cell apoptosis. It revealed ORI resistant breast cancer action target point, studied its anti breast cancer mechanism, the clinical application of ORI treatment of breast cancer and lay the theoretical foundation.
Methods:
(A). In vitro experiments: The inhibition effect of different concentrations(10μmol/L、20μmol/L、40μmol/L、80μmol/L and160μmol/L) of ORI on MCF-7cell proliferation on different times was tested(24h、48h and72h);
The comet assay for the detection of single cell DNA damage; Immunofluorescence assay for the detection of r-h2ax, p-ATM protein expression; PI single staining and flow cytometry for cell cycle distribution; Annexin V-FITC/PI double-labeled apoptosis with flow cytometry and Western blot for detection of cell cycle arrest and apoptosis related protein expression; Transmission electron microscopic was hired for observation of cell morphology using ultrathin sections.
(B). In vivo experiments:
The mouse acute toxicity test for the detection of ORI medication safety:Human breast cancer MCF-7cells were inoculated into nude mice under the armpit,7days after transplantation tumor in nude mice will get tumors about4mm-5mm in diameter, that means transplantation was successfully established;
Giving ORI for14consecutive days and then measured the average tumor weight in the control group and the test group and calculation of the tumor inhibition rate:Dissection of each tumor tissue and making a cell morphological examination; Detection of apoptotic cells in nude mice by TUNEL test;
Double staining flow cytometry of cells apoptosis in nude mice transplanted tumor rate; Using western-blot detecting cells apoptosis in nude mice transplanted tumor associated protein expression.
Results
Resuls in vitro:
(1). The inhibition effect of different concentrations (10μmol/L、20μmol/L、40μmol/L、80μmol/L and160μmol/L) of ORI on MCF-7cell proliferation on different times (24h、48h and72h) was tested and the results showed:ORI has a direct inhibitory effect on MCF-7cells in vitro, which is in a time and dose dependent. The IC50of ORI to MCF7cells is78.3μmol/L after ORI was applied to it after48hours;
(2).The comet assay showed, at concentration of80μmol/L and160μmol/L after48h applied, ORI can induce the DNA damage of MCF-7cells and it showed a dose-effect relationship;
(3). Immunofluorescence experiments showed that ORI can induce the increase of expression of r-h2ax and p-ATM proteins of MCF7cells at concentration of80μmol/L and160μmol/L after48h applied,;
(4). Flow cytometry in cell cycle distribution showed that ORI induced MCF7stagnation in G2phase of cell cycle at concentration of10μmol/L、20μmol/L、40μmol/L、80μmol/L and160μmol/L after48h with a dose-dependent relationship;
(5). Flow cytometry apoptosis detection kit (Annexin V-FITC) showed that the ORI can induce apoptosis in MCF-7cells and the rate of apoptosis is dose-dependent at concentration of10μmol/L、20μmol/L、40μmol/L、80μmol/L and160μmol/L after72h;
(6). Western blotting protein detection showed that, at concentration of10μmol/L20μmol/L、40μmol/L、80μmol/L and160μmol/L after48h, ORI can up-regulate the protein expressions of p-ATM、r-H2AX、p-CHK2、p-Cdc2、p-Cdc25C and Cycling Bl. It prompted that ORI may induced MCF7stagnation in G2/M phase of cell cycle and then induced cell cycle arrest through ATM-p53-p21WAF1/CIP1and ATM-Chk2-Cdc25C signal pathway;
(7). Western blotting protein detection showed that, at concentration of10μmol/L20μmol/L、40μmol/L、80μmol/L and160μmol/L after72h, ORI can make down-regulation of the expression of Bcl-12protein and up-regulation of the expression of Bax、Fas and cleaved-caspase3proteins with a dose-dependently pattern and reduce the rate of Bcl-2/Bax. The above results implicated that ORI induced some special proteins expression of MCF-7cells may through the road of decease of the receptors and chondriosomes;
(8). By ultrathin sections, transmission electron microscopy showed ORI can induce a representative MCF-7cells apoptosis at concentration of80μmol/L and160μmol/L after72h.
Results in vivo experiments:
(1). The mouse acute toxicity test showed that the mouse liver and kidney either their structure or function index are within the normal stage after treatment. Results indicated that, ORI, on organism level, has no obvious side effect ant it is in a high safety of medication.
(2). We made a successful establishment of human breast carcinoma model in nude mice as the human breast cancer MCF-7cell can be vaccinated in nude mice;
(3). The tumor inhibition rates of ORI (High) group and ORI (Low) group were36.7%and34.6%specially and there is a significantly difference compared with the control group(p<0.01);
(4). Tumor cells decreased obviously after giving ORI and CTX. The tumor cells heteromorphism showed a trend from the low differentiation to moderately differentiation and a massive necrosis of tumor cells and the reversion of malignant phenotypes was found;
(5). Result of TUNEL method test showed that ORI can induce apoptosis of tumor cells in vivo;
(6). The percentage of apoptotic cells of ORI (L)、ORI (H) and CTX group are17.02±4.98%、22.37±6.43%and27.46±6.09%respectively. There are significantly differences compared ORI (H) and CTX groups with the control group (6.24+-2.32%).(p<0.05and0.01);
(7). By Annexin V-FITC/PI double-labeled apoptosis with flow cytometry test, the results showed that the percentage of apoptotic cells of ORI(L、ORI (H) and CTX group are32.60%、14.23%and26.73%respectively. There are significantly differences in apoptosis rate compared with the control group (p<0.05and p<0.01);
(8). ORI can increase the proteins expressions of cleaved Caspase-3、cleaved Caspase-8、 cleaved Caspase-9、Fas、Cyt-c and Bax in dose-dependent. ORI can induce transplant tumor cells apoptosis through the road of decease of the receptors and chondriosomes.
Conclusion:Our research demonstrates that oridonin have the effect of anti-breast cancer in vivo and vitro, the mechanism of which involves inhibiting cancer cells growth through inducing cell cycle arrest and promoting cell apoptosis by inducing the activation of the Fas signal transduction pathway and the mitochondria pathway. Oridonin has no obvious side effect and it is expected to be used in clinical treatment for breast cancer in the near future.
引文
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