健脾益肺化瘀方对肺癌耐药逆转及其基因表达影响的研究
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摘要
目的：探讨健脾益肺化瘀方对肺癌的抑制和对化疗药物的协同增效及耐药逆转作用，为临床提高肺癌疗效提供客观的实验依据。
方法：以动物移植性Lewis肺癌为模型，观察健脾益肺化瘀方的抑瘤率，及对化疗药物顺铂(DDP)抑瘤的协同增效作用；以人肺腺癌敏感细胞A549和耐药细胞A549／DDP为研究对象，采用细胞毒实验(MTT)、流式细胞仪(FCM)法，观察健脾益肺化瘀方含药血清对A549和A549／DDP的细胞毒作用、细胞周期的影响，及对A549／DDP多药耐药相关蛋白(MRP)、拓扑异构酶Ⅱ(TopoⅡ)和谷胱甘肽S转移酶(GST)表达的影响，同时观察与维拉帕米(VPL)合用对肺癌耐药性的协同逆转作用。
结果：健脾益肺化瘀方对动物移植性Lewis肺癌有显著的抑制作用，并能增强DDP的抑瘤率。健脾益肺化瘀方含药血清对A549和A549／DDP均有一定的细胞毒作用，能使A549和A549／DDP G_1期细胞比例显著增高、S期细胞比例显著降低，并能显著抑制A549／DDP细胞内MRP和GST的表达，而增强TopoⅡ的活性(P＜0.05)；且与维拉帕米均能逆转A549／DDP的耐药性，而且联合使用具有协同作用。
结论：健脾益肺化瘀方对动物移植性肺癌具有抑瘤作用，能阻滞肺癌细胞进入增殖期，从而达到抑制肺癌细胞生长的目的；并能增强DDP的敏感性和具有对DDP的耐药逆转作用，其作用机理与健脾益肺化瘀方抑制A549／DDP耐药基因MRP和GST的表达和增强TopoⅡ活性密切相关。
Objective: To Study on effects of Jianpi Yifei Huayu(JPYFHY) Recipe to inhibite the tumor of lung cancer and enhance the synergism of DDP, and reverse multidrug resistance of lung cancer chemotherapy, in order to provide objective experimental evidence for enhancing synergism of lung cancer in clinic.
Methods: The model of Lewis lung cancer transplanted animals were applied to study the effects of tumor inhibition and synergism of enhancing the chemotherapeutic agents Cisplatinum(DDP). We take the lung cancer sensitivity cell A549 and resistance cell A549 / DDP for research object to observe the influnence cytotoxicity effects of JPYFHY Recipe drug-serum to the A549 and A549 / DDP, just as the cytotoxicity effects, and the influnence to cell cycle and the resistance reversion to DDP, which are determined by MTT assay. The expression of Multidrug resistance protein (MRP), TopoisomeraseⅡ(TopoⅡ)and Glutathione Stransferases(GST)ofA549 / DDP, are determined by Flow cytometry(FCM)respectively. At the same time, We observer the synergical reversion effects on drug resistance lung cancer when JPYFHY Recipe are combined with VPL in using.
Result: The results show that JPYFHY Recipe had remarkably restraining effects, and it can significantly increase the inhibition rate of DDP to transplanted Lewis lung cancer. JPYFHY Recipe drug-serum has a certain cytotoxicities effects to A549 and A549 / DDP, and results in progressive increase in cells in G_1 phase and decrease in cells in S phase of the cell cycle. It can also significantly restrain the expression of MRP and GST, but enhance the activity of TopoⅡin multidrug resistance lung cancer cells. Lastly, JPYFHY Recipe and VPL both can reverse the drug resistance ofA549 / DDP, and the drugs can insert synergical effects when they are used in combination.
Conclusions: JPYFHY Recipe can inhibite the tumor of lung cancer transplanted animals, and the JPYFHY Recipe drug-serum can block the prolife ration of A549/DDP in vitro by inducing cancer cell apoptoses and boking cell cycle; It can enhance the chemotherapy synergism effects when they are used in combination and reverse multidrug resistance which because of DDP. The mechanism of these reversing drug resistance maybe is related to downregulating the expression of MRP and GST and upregulating the expression of TopoⅡ.
方法：以动物移植性Lewis肺癌为模型，观察健脾益肺化瘀方的抑瘤率，及对化疗药物顺铂(DDP)抑瘤的协同增效作用；以人肺腺癌敏感细胞A549和耐药细胞A549／DDP为研究对象，采用细胞毒实验(MTT)、流式细胞仪(FCM)法，观察健脾益肺化瘀方含药血清对A549和A549／DDP的细胞毒作用、细胞周期的影响，及对A549／DDP多药耐药相关蛋白(MRP)、拓扑异构酶Ⅱ(TopoⅡ)和谷胱甘肽S转移酶(GST)表达的影响，同时观察与维拉帕米(VPL)合用对肺癌耐药性的协同逆转作用。
结果：健脾益肺化瘀方对动物移植性Lewis肺癌有显著的抑制作用，并能增强DDP的抑瘤率。健脾益肺化瘀方含药血清对A549和A549／DDP均有一定的细胞毒作用，能使A549和A549／DDP G_1期细胞比例显著增高、S期细胞比例显著降低，并能显著抑制A549／DDP细胞内MRP和GST的表达，而增强TopoⅡ的活性(P＜0.05)；且与维拉帕米均能逆转A549／DDP的耐药性，而且联合使用具有协同作用。
结论：健脾益肺化瘀方对动物移植性肺癌具有抑瘤作用，能阻滞肺癌细胞进入增殖期，从而达到抑制肺癌细胞生长的目的；并能增强DDP的敏感性和具有对DDP的耐药逆转作用，其作用机理与健脾益肺化瘀方抑制A549／DDP耐药基因MRP和GST的表达和增强TopoⅡ活性密切相关。
Objective: To Study on effects of Jianpi Yifei Huayu(JPYFHY) Recipe to inhibite the tumor of lung cancer and enhance the synergism of DDP, and reverse multidrug resistance of lung cancer chemotherapy, in order to provide objective experimental evidence for enhancing synergism of lung cancer in clinic.
Methods: The model of Lewis lung cancer transplanted animals were applied to study the effects of tumor inhibition and synergism of enhancing the chemotherapeutic agents Cisplatinum(DDP). We take the lung cancer sensitivity cell A549 and resistance cell A549 / DDP for research object to observe the influnence cytotoxicity effects of JPYFHY Recipe drug-serum to the A549 and A549 / DDP, just as the cytotoxicity effects, and the influnence to cell cycle and the resistance reversion to DDP, which are determined by MTT assay. The expression of Multidrug resistance protein (MRP), TopoisomeraseⅡ(TopoⅡ)and Glutathione Stransferases(GST)ofA549 / DDP, are determined by Flow cytometry(FCM)respectively. At the same time, We observer the synergical reversion effects on drug resistance lung cancer when JPYFHY Recipe are combined with VPL in using.
Result: The results show that JPYFHY Recipe had remarkably restraining effects, and it can significantly increase the inhibition rate of DDP to transplanted Lewis lung cancer. JPYFHY Recipe drug-serum has a certain cytotoxicities effects to A549 and A549 / DDP, and results in progressive increase in cells in G_1 phase and decrease in cells in S phase of the cell cycle. It can also significantly restrain the expression of MRP and GST, but enhance the activity of TopoⅡin multidrug resistance lung cancer cells. Lastly, JPYFHY Recipe and VPL both can reverse the drug resistance ofA549 / DDP, and the drugs can insert synergical effects when they are used in combination.
Conclusions: JPYFHY Recipe can inhibite the tumor of lung cancer transplanted animals, and the JPYFHY Recipe drug-serum can block the prolife ration of A549/DDP in vitro by inducing cancer cell apoptoses and boking cell cycle; It can enhance the chemotherapy synergism effects when they are used in combination and reverse multidrug resistance which because of DDP. The mechanism of these reversing drug resistance maybe is related to downregulating the expression of MRP and GST and upregulating the expression of TopoⅡ.
引文
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