生长抑素类似物对非小细胞肺癌耐药细胞株靶向治疗作用的实验研究
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摘要
目的:探讨生长抑素类似物奥曲肽在体外对人非小细胞肺癌(non-small celllung cancer,NSCLC)细胞的抑制作用及奥曲肽对NSCLC化疗是否具有增敏作用,并研究其可能的机制;通过三种不同方式建立对紫杉醇耐药的非小细胞肺癌耐药细胞系,并探讨其耐药机制;合成奥曲肽紫杉醇耦连物并研究其由生长抑素受体(somatostatin receptor,SSTR)介导的对NSCLC耐药细胞株的靶向治疗作用。
方法:RT-PCR检测非小细胞肺癌细胞株A549和H157 SSTR 1-5 mRNA的表达;检测不同时间和浓度梯度的奥曲肽对两细胞株的抑制率;光镜下观测奥曲肽作用后的细胞形态学变化;MTT法检测奥曲肽与紫杉醇对两细胞株是否具有协同作用;采用流式细胞仪检测奥曲肽、紫杉醇以及两者联合作用时A549细胞的凋亡率;荧光实时定量PCR检测奥曲肽作用后细胞多药耐药相关基因的改变。
分别采用紫杉醇大剂量冲击诱导法、大剂量冲击序贯小剂量诱导法和小剂量逐步诱导法分别诱导非小细胞肺癌细胞株A549,建立非小细胞肺癌紫杉醇耐药细胞株A549-P、A549-PS和A549-S;倒置显微镜观察并记录细胞形态;细胞计数法观测细胞增值规律;MTT法计算IC50和RI;流式细胞仪检测细胞周期分布;MTT法检测耐药细胞系的多药耐药性;实时定量PCR检测多药耐药相关基因MDR-1、MRP-1、BCRP等mRNA的相对表达量。
采用液相有机合成的方法,合成奥曲肽紫杉醇耦连物;并采用MTT法研究其对A549及其耐药细胞株的靶向治疗作用。
结果:A549细胞检测到SSTR1～SSTR5 mRNA的表达,而H157细胞除有SSTR1和SSTR4 mRNA的表达外,其他受体均未检测到mRNA的表达。奥曲肽对A549细胞增殖具有抑制作用并具有时间(24h、48h、72h)和浓度(1～1000nmol/L)依赖性,在光镜下可观测到细胞细胞受损伤的形态学改变;而对H157细胞无抑制作用。对于A549细胞,125、250、500nmol/L奥曲肽作用48h可明显增加其对化疗的敏感性(P＜0.01);并能诱导细胞凋亡,但未增加与紫杉醇联合作用后细胞的凋亡率;而对H157细胞,奥曲肽未发现化疗增敏作用。奥曲肽可下调A549细胞多药耐药相关基因MDR-1、MRP-1的表达(P＜0.05,P＜0.01),而对H157细胞多药耐药相关基因的表达无影响。
成功建立了A549-P、A549-PS和A549-S三种非小细胞肺癌紫杉醇耐药细胞系,其耐药指数分别为6.48、77.84和9.98,并伴有细胞形态、生长增殖和细胞周期的改变;A549-S的MDR-1、MRP-1、BCRP均有不同程度的升高;A549-PS的MDR-1和A549/P的MRP-1也升高,而其他耐药基因则下调。
成功得到了紫杉醇中间体(PTX-L),以及奥曲肽紫杉醇耦连物PTX-OCT和2PTX-OCT;奥曲肽紫杉醇耦连物PTX-OCT、2PTX-OCT对三种耐药细胞株的作用强于PTX,特别是对于A549-S耐药细胞株。
结论:奥曲肽可增加SSTR受体阳性的非小细胞肺癌细胞的化疗敏感性,下调多药耐药的表达是其可能的机制之一。
不同诱导方式建立的耐药细胞系之间存在差异;非小细胞肺癌的紫杉醇耐药涉及多药耐药基因的改变等多方面的因素。
由生长抑素受体介导的奥曲肽紫杉醇耦连物对非小细胞肺癌耐药细胞株的靶向治疗作用强于紫杉醇的作用,可能具有逆转耐药的作用。
OBJECTIVE: To investigate whether octreotide can potentiate the anti-proliferative effect of paclitaxel on non-small cell lung cancer and explore possible mechanisms.
Three NSCLC drug-resistant cell lines were established by different approaches to compare their biological characteristics and elucidate possible mechanisms of drug resistance.
METHODS: The mRNA expression of Somatostatin Receptor(SSTR)1-5 in non-small cell lung cancer cell lines A549 and H157 was evaluated by RT-PCR. The inhibitory effect of octreotide on the growth of A549 and H157 cells was evaluated by MTT assay and the morphological changes after octreotide treatment was observed by microscopy. MTT assay was also used to investigate whether combinations of octreotide and paclitaxel resulted in synergistic interactions. Cell apoptosis of A549 cell after treatment with paclitaxel, octroetide, and combinations of octreotide and paclitaxel was analysed by flow cytometry .The changes of MDR-1, MRP-1, BCRP mRNA expression of the cells after treatment with octreotide was evaluated by real time PCR.
Three NSCLC paclitaxel-resistant cell lines:A549-P,A549-PS and A549-S were established respectively by high dose pulse, high dose pulse followed by low dose exposure in a stepwise manner and only low dose exposure in a stepwise manner. The biological characteristics of cell lines were determined by microscopy and cell count assay.The drug resistance to paclitaxel and cross resistance to adriamycin, vincristine and CDDP were determined by MTT assay. The cell cycle was detected by flow cytometry. The relative mRNA expression of MDR-1,MRP-1 and BCRP was evaluated by real time PCR.
Three kinds of paclitaxel-octreotide conjugates were synthenized and their targeting inhibitory effects on the NSCLC paclitaxel-resistant cells were evaluated by MTT.
RESULTS: The mRNA expression of SSTR1～SSTR5 was detected in A549 cells, while only mRNA expression of SSTR1 and SSTR4 was detected in H157 cells. Octreotide had an inhibitory effect on A549 cells in a time (24h, 48h, 72h) and dose(1～1000nmol/L)-dependent manner and morphological changes of the injured cells were observed; while it had no effect on H157 cells. The dose-dependent anti-proliferative effect of paclitaxel was synergistically enhanced by octreotide (125nmol/L, 250nmol/L, 500 nmol/L)on A549 cells(P<0.01); but for H157 cells , combination of octreotide and paclitaxel resulted in additive interactions. Cell apoptosis was induced by octreotide in A549 cells, but the apoptosis induced by paclitaxel was not promoted by octreotide in A549 cells. The mRNA expression of MDR-1, MRP-1 was down-regulated after octreotide treatment in A549 cells(P<0.05, P<0.01), while there were no changes in H157 cells.
The resistance indexes of A549-P, A549-PS and A549-S were 6.48, 77.84 and 9.98 and there were changes in their biological characteristics. The mRNA expression of MDR-1, MRP-1 and BCRP were up-regulated in A549-S;and the mRNA expression of MDR-1 in A549-PS and MRP-1 in A549-P were also up-regulated.Other multidrug resistance genes were down-regulated.
PTX-linker, PTX-OCT, and 2PTX-OCT were synthenized; and they had much stonger inhibitory effects on the NSCLC paclitaxel-resistant cells.
CONCLUSION: Octreotide can promote the anti-proliferative effect of paclitaxel on SSTR-positive non-small cell lung cancer in synergy; and down-regulation of multidrug related genes may be the possible mechanism.
There wad difference between three paclitaxel-resistant cell lines induced by different approaches and the changes of multidrug resistance genes may be involved in the mechanism of drug resistance.
The paclitaxel-octreotide conjugates had targeted inhibitory effects on the NSCLC paclitaxel-resistant cells and might reverse the drug resistance of paclitaxel.
方法:RT-PCR检测非小细胞肺癌细胞株A549和H157 SSTR 1-5 mRNA的表达;检测不同时间和浓度梯度的奥曲肽对两细胞株的抑制率;光镜下观测奥曲肽作用后的细胞形态学变化;MTT法检测奥曲肽与紫杉醇对两细胞株是否具有协同作用;采用流式细胞仪检测奥曲肽、紫杉醇以及两者联合作用时A549细胞的凋亡率;荧光实时定量PCR检测奥曲肽作用后细胞多药耐药相关基因的改变。
分别采用紫杉醇大剂量冲击诱导法、大剂量冲击序贯小剂量诱导法和小剂量逐步诱导法分别诱导非小细胞肺癌细胞株A549,建立非小细胞肺癌紫杉醇耐药细胞株A549-P、A549-PS和A549-S;倒置显微镜观察并记录细胞形态;细胞计数法观测细胞增值规律;MTT法计算IC50和RI;流式细胞仪检测细胞周期分布;MTT法检测耐药细胞系的多药耐药性;实时定量PCR检测多药耐药相关基因MDR-1、MRP-1、BCRP等mRNA的相对表达量。
采用液相有机合成的方法,合成奥曲肽紫杉醇耦连物;并采用MTT法研究其对A549及其耐药细胞株的靶向治疗作用。
结果:A549细胞检测到SSTR1～SSTR5 mRNA的表达,而H157细胞除有SSTR1和SSTR4 mRNA的表达外,其他受体均未检测到mRNA的表达。奥曲肽对A549细胞增殖具有抑制作用并具有时间(24h、48h、72h)和浓度(1～1000nmol/L)依赖性,在光镜下可观测到细胞细胞受损伤的形态学改变;而对H157细胞无抑制作用。对于A549细胞,125、250、500nmol/L奥曲肽作用48h可明显增加其对化疗的敏感性(P＜0.01);并能诱导细胞凋亡,但未增加与紫杉醇联合作用后细胞的凋亡率;而对H157细胞,奥曲肽未发现化疗增敏作用。奥曲肽可下调A549细胞多药耐药相关基因MDR-1、MRP-1的表达(P＜0.05,P＜0.01),而对H157细胞多药耐药相关基因的表达无影响。
成功建立了A549-P、A549-PS和A549-S三种非小细胞肺癌紫杉醇耐药细胞系,其耐药指数分别为6.48、77.84和9.98,并伴有细胞形态、生长增殖和细胞周期的改变;A549-S的MDR-1、MRP-1、BCRP均有不同程度的升高;A549-PS的MDR-1和A549/P的MRP-1也升高,而其他耐药基因则下调。
成功得到了紫杉醇中间体(PTX-L),以及奥曲肽紫杉醇耦连物PTX-OCT和2PTX-OCT;奥曲肽紫杉醇耦连物PTX-OCT、2PTX-OCT对三种耐药细胞株的作用强于PTX,特别是对于A549-S耐药细胞株。
结论:奥曲肽可增加SSTR受体阳性的非小细胞肺癌细胞的化疗敏感性,下调多药耐药的表达是其可能的机制之一。
不同诱导方式建立的耐药细胞系之间存在差异;非小细胞肺癌的紫杉醇耐药涉及多药耐药基因的改变等多方面的因素。
由生长抑素受体介导的奥曲肽紫杉醇耦连物对非小细胞肺癌耐药细胞株的靶向治疗作用强于紫杉醇的作用,可能具有逆转耐药的作用。
OBJECTIVE: To investigate whether octreotide can potentiate the anti-proliferative effect of paclitaxel on non-small cell lung cancer and explore possible mechanisms.
Three NSCLC drug-resistant cell lines were established by different approaches to compare their biological characteristics and elucidate possible mechanisms of drug resistance.
METHODS: The mRNA expression of Somatostatin Receptor(SSTR)1-5 in non-small cell lung cancer cell lines A549 and H157 was evaluated by RT-PCR. The inhibitory effect of octreotide on the growth of A549 and H157 cells was evaluated by MTT assay and the morphological changes after octreotide treatment was observed by microscopy. MTT assay was also used to investigate whether combinations of octreotide and paclitaxel resulted in synergistic interactions. Cell apoptosis of A549 cell after treatment with paclitaxel, octroetide, and combinations of octreotide and paclitaxel was analysed by flow cytometry .The changes of MDR-1, MRP-1, BCRP mRNA expression of the cells after treatment with octreotide was evaluated by real time PCR.
Three NSCLC paclitaxel-resistant cell lines:A549-P,A549-PS and A549-S were established respectively by high dose pulse, high dose pulse followed by low dose exposure in a stepwise manner and only low dose exposure in a stepwise manner. The biological characteristics of cell lines were determined by microscopy and cell count assay.The drug resistance to paclitaxel and cross resistance to adriamycin, vincristine and CDDP were determined by MTT assay. The cell cycle was detected by flow cytometry. The relative mRNA expression of MDR-1,MRP-1 and BCRP was evaluated by real time PCR.
Three kinds of paclitaxel-octreotide conjugates were synthenized and their targeting inhibitory effects on the NSCLC paclitaxel-resistant cells were evaluated by MTT.
RESULTS: The mRNA expression of SSTR1～SSTR5 was detected in A549 cells, while only mRNA expression of SSTR1 and SSTR4 was detected in H157 cells. Octreotide had an inhibitory effect on A549 cells in a time (24h, 48h, 72h) and dose(1～1000nmol/L)-dependent manner and morphological changes of the injured cells were observed; while it had no effect on H157 cells. The dose-dependent anti-proliferative effect of paclitaxel was synergistically enhanced by octreotide (125nmol/L, 250nmol/L, 500 nmol/L)on A549 cells(P<0.01); but for H157 cells , combination of octreotide and paclitaxel resulted in additive interactions. Cell apoptosis was induced by octreotide in A549 cells, but the apoptosis induced by paclitaxel was not promoted by octreotide in A549 cells. The mRNA expression of MDR-1, MRP-1 was down-regulated after octreotide treatment in A549 cells(P<0.05, P<0.01), while there were no changes in H157 cells.
The resistance indexes of A549-P, A549-PS and A549-S were 6.48, 77.84 and 9.98 and there were changes in their biological characteristics. The mRNA expression of MDR-1, MRP-1 and BCRP were up-regulated in A549-S;and the mRNA expression of MDR-1 in A549-PS and MRP-1 in A549-P were also up-regulated.Other multidrug resistance genes were down-regulated.
PTX-linker, PTX-OCT, and 2PTX-OCT were synthenized; and they had much stonger inhibitory effects on the NSCLC paclitaxel-resistant cells.
CONCLUSION: Octreotide can promote the anti-proliferative effect of paclitaxel on SSTR-positive non-small cell lung cancer in synergy; and down-regulation of multidrug related genes may be the possible mechanism.
There wad difference between three paclitaxel-resistant cell lines induced by different approaches and the changes of multidrug resistance genes may be involved in the mechanism of drug resistance.
The paclitaxel-octreotide conjugates had targeted inhibitory effects on the NSCLC paclitaxel-resistant cells and might reverse the drug resistance of paclitaxel.
引文
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[2]Dimitroulopoulos D, Xinopoulos D, Tsamakidis K,et al. Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: randomized placebo-controlled trial[J]. World J Gastroenterol.2007 Jun 21 ;13(23):3164-70.
[3] Tjomsland V, El-Salhy M. Anti-tumour effects of triple therapy with octreotide, galanin and serotonin in comparison with those of 5-fluorouracil/leukovorin on human colon cancer[J]. Int J Oncol. 2005 Aug;27(2):427-32.
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