羧胺三唑对乳腺癌细胞的生长抑制作用及其机制研究
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摘要
研究背景
羧胺三唑(carboxyamidotriazole，CAI)是一种钙离子跨膜内流抑制剂，也是细胞内多种需要钙离子参与的信号转导通路的抑制剂。体外研究发现，CAI具有抑制多种肿瘤细胞系的增殖、侵袭和转移的特性。这些肿瘤细胞系包括前列腺癌、胶质母细胞瘤、膀胱癌、肝癌、白血病以及乳腺癌等。在鸡胚脲囊素膜检测和大鼠动脉环分析实验中，CAI表现出抑制血管生成的活性。另外，CAI还能够抑制人脐静脉内皮细胞(human umbilical vein endothelial cells，HUVEC)的增殖。近来也有研究证实，CAI能够诱导细胞凋亡从而抑制肿瘤细胞的增殖。
尽管许多研究对CAI的抗增殖、抗血管生成、抗转移以及诱导细胞凋亡的作用进行了很好的阐述，但是，CAI自身对肿瘤细胞细胞周期的调节作用尚未见报道。而且，人们对于CAI抗肿瘤作用的具体分子机制还了解甚少。因此，我们此项研究的目的就是检测CAI对人乳腺癌MCF-7细胞以及转染了SV40大T抗原的293T细胞的增殖抑制活性，探讨CAI诱导乳腺癌细胞周期阻滞和诱发细胞凋亡的信号转导通路，为目前正在开展的临床试验，以及CAI作为人乳腺癌的预防或治疗用药提供理论依据。
研究方法
我们采用台盼蓝染料排斥实验和四唑盐(MTT)分析法来检测CAI对细胞存活率的影响。通过相差显微镜观察CAI处理后MCF-7细胞的形态学变化。通过[~3H]-胸腺嘧啶掺入实验来分析CAI对细胞DNA合成的影响。另外，对细胞进行碘化丙啶染色，利用流式细胞仪检测细胞的DNA含量，评价CAI对细胞周期分布的影响。CAI对MCF-7细胞的凋亡诱导作用通过两种方法测定：应用流式细胞仪分析细胞的亚二倍体凋亡峰以及使用annexin V-FITC／PI凋亡检测试剂盒定量分析磷脂酰丝氨酸外翻。采用Rhodamine 123染色，流式细胞技术检测CAI长期孵育对线粒体膜电势的影响。利用荧光素—荧光素酶生物发光分析法检测细胞内的ATP含量。进行Western blot，
Background.
Carboxyamidotriazole (CAI) is an inhibitor of transmembrane calcium influx and intracellular calcium-requiring signal transduction pathway. CAI inhibits the proliferation and invasive characteristics of several tumor cell lines in vitro, including prostate, glioblastoma, bladder, hepatoma, leukemia and breast. CAI also demonstrates antiangiogenic activity in the chick chorioallantotic membrane assay and rat aortic ring assay, as well as the activity of inhibiting the proliferation of human umbilical vein endothelial cells in vitro. Recent studies have indicated that CAI can inhibit proliferation of
cultured cancer cells by inducing apoptosis.
Although the antiproliferative, antiangiogenic, anti-invasive and apoptosis inductive effects of CAI have been well-documented, the cell cycle regulating activity of CAI itself in cancer cells has not been systematically assessed. And little is known about the molecular mechanism of the anticancer effect of CAI. The purpose of our present study is to evaluate the antiproliferative activity of CAI against MCF-7 human breast cancer cells and 293T cells, explore the mechanisms and signaling pathways of CAI-induced cell cycle arrest and apoptosis in human breast cancer cells and provide basic evidence for on-going clinical trial and the applicability of CAI as a potential preventive and/or therapeutic agent against human breast cancer.
Methods.
Survival/proliferation of cell lines treated with CAI was determined by trypan blue dye exclusion assay or MTT assay. The morphological changes of MCF-7 cells were observed and photographed by a phase-contrast microscope. [~3H]-thymidine incorporation assay was performed to assess DNA synthesis of cells. Cell cycle distribution was determined by flow cytometric analysis of DNA content of nuclei of cells following staining with propidium iodide. Apoptosis induction by CAI in MCF-7 cells was assessed by (i) flow cytometry analysis of sub-G_0-G_1 DNA content and (ii) quantification of phosphatidylserine exposure using annexin V-FITC kit. Alterations in mitochondrial membrane potential (△ψ_m) were analyzed by flow cytometry using the △ψ_m-sensitive dye rhodamine123.
羧胺三唑(carboxyamidotriazole，CAI)是一种钙离子跨膜内流抑制剂，也是细胞内多种需要钙离子参与的信号转导通路的抑制剂。体外研究发现，CAI具有抑制多种肿瘤细胞系的增殖、侵袭和转移的特性。这些肿瘤细胞系包括前列腺癌、胶质母细胞瘤、膀胱癌、肝癌、白血病以及乳腺癌等。在鸡胚脲囊素膜检测和大鼠动脉环分析实验中，CAI表现出抑制血管生成的活性。另外，CAI还能够抑制人脐静脉内皮细胞(human umbilical vein endothelial cells，HUVEC)的增殖。近来也有研究证实，CAI能够诱导细胞凋亡从而抑制肿瘤细胞的增殖。
尽管许多研究对CAI的抗增殖、抗血管生成、抗转移以及诱导细胞凋亡的作用进行了很好的阐述，但是，CAI自身对肿瘤细胞细胞周期的调节作用尚未见报道。而且，人们对于CAI抗肿瘤作用的具体分子机制还了解甚少。因此，我们此项研究的目的就是检测CAI对人乳腺癌MCF-7细胞以及转染了SV40大T抗原的293T细胞的增殖抑制活性，探讨CAI诱导乳腺癌细胞周期阻滞和诱发细胞凋亡的信号转导通路，为目前正在开展的临床试验，以及CAI作为人乳腺癌的预防或治疗用药提供理论依据。
研究方法
我们采用台盼蓝染料排斥实验和四唑盐(MTT)分析法来检测CAI对细胞存活率的影响。通过相差显微镜观察CAI处理后MCF-7细胞的形态学变化。通过[~3H]-胸腺嘧啶掺入实验来分析CAI对细胞DNA合成的影响。另外，对细胞进行碘化丙啶染色，利用流式细胞仪检测细胞的DNA含量，评价CAI对细胞周期分布的影响。CAI对MCF-7细胞的凋亡诱导作用通过两种方法测定：应用流式细胞仪分析细胞的亚二倍体凋亡峰以及使用annexin V-FITC／PI凋亡检测试剂盒定量分析磷脂酰丝氨酸外翻。采用Rhodamine 123染色，流式细胞技术检测CAI长期孵育对线粒体膜电势的影响。利用荧光素—荧光素酶生物发光分析法检测细胞内的ATP含量。进行Western blot，
Background.
Carboxyamidotriazole (CAI) is an inhibitor of transmembrane calcium influx and intracellular calcium-requiring signal transduction pathway. CAI inhibits the proliferation and invasive characteristics of several tumor cell lines in vitro, including prostate, glioblastoma, bladder, hepatoma, leukemia and breast. CAI also demonstrates antiangiogenic activity in the chick chorioallantotic membrane assay and rat aortic ring assay, as well as the activity of inhibiting the proliferation of human umbilical vein endothelial cells in vitro. Recent studies have indicated that CAI can inhibit proliferation of
cultured cancer cells by inducing apoptosis.
Although the antiproliferative, antiangiogenic, anti-invasive and apoptosis inductive effects of CAI have been well-documented, the cell cycle regulating activity of CAI itself in cancer cells has not been systematically assessed. And little is known about the molecular mechanism of the anticancer effect of CAI. The purpose of our present study is to evaluate the antiproliferative activity of CAI against MCF-7 human breast cancer cells and 293T cells, explore the mechanisms and signaling pathways of CAI-induced cell cycle arrest and apoptosis in human breast cancer cells and provide basic evidence for on-going clinical trial and the applicability of CAI as a potential preventive and/or therapeutic agent against human breast cancer.
Methods.
Survival/proliferation of cell lines treated with CAI was determined by trypan blue dye exclusion assay or MTT assay. The morphological changes of MCF-7 cells were observed and photographed by a phase-contrast microscope. [~3H]-thymidine incorporation assay was performed to assess DNA synthesis of cells. Cell cycle distribution was determined by flow cytometric analysis of DNA content of nuclei of cells following staining with propidium iodide. Apoptosis induction by CAI in MCF-7 cells was assessed by (i) flow cytometry analysis of sub-G_0-G_1 DNA content and (ii) quantification of phosphatidylserine exposure using annexin V-FITC kit. Alterations in mitochondrial membrane potential (△ψ_m) were analyzed by flow cytometry using the △ψ_m-sensitive dye rhodamine123.
引文
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王洪领 抗肿瘤新药羧胺三唑抑制细胞增殖机制的初步研究 博士论文 2005
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