生长抑素受体介导的靶向治疗对非小细胞肺癌耐药的逆转作用及其机制研究
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摘要
目的:检测人非小细胞肺癌(non-small cell lung cancer,NSCLC)组织SSTR2和SSTR5的表达,并分析其与患者病理分期、预后的关系;合成奥曲肽紫杉醇偶联物,检测人非小细胞肺癌细胞株生长抑素受体(Somatostatin Receptors,SSTRs)的表达,并验证不同结构的奥曲肽紫杉醇偶联物是否对其具有靶向治疗作用;采用不用方式诱导建立非小细胞肺癌耐药细胞株,并检测奥曲肽紫杉醇偶联物对其耐药的逆转作用;探讨奥曲肽紫杉醇偶联物逆转耐药的可能机制。研究奥曲肽紫杉醇偶联物在体外及体内作用于NSCLC后对其多药耐药相关基因表达的影响,探讨其是否能延缓或降低肿瘤耐药的产生。
方法:免疫组化检测人非小细胞肺癌组织SSTR2和SSTR5的表达;采用RT-PCR从mRNA水平检测人非小细胞肺癌细胞株A549和H157 SSTRs的表达;采用MTT和流式细胞术检测奥曲肽紫杉醇偶联物对两细胞株的毒性和凋亡的影响;同时采用MTT检测偶联物能否逆转不用方式诱导建立的耐药细胞株对紫杉醇的耐药作用;流式细胞术分析耐药细胞株的周期分布,实时定量PCR检测其SSTRs和多药耐药相关基因的表达,探讨偶联物逆转耐药的可能机制;实时定量PCR检测紫杉醇及其偶联物在体外及体内作用于A549细胞后其多药耐药相关基因的表达。
结果:SSTR2和SSTR5在NSCLC组织的表达率分别为62.7%和61.0%,在癌旁组织的表达率分别为为13.33%(2/15)和20.00%(3/15)。SSTR2、SSTR5蛋白表达与NSCLC的TNM分期有密切关系(P＜0.05),其表达增高提示预后较好,生存期长;但与患者的年龄、性别、吸烟与否、病理类型、肿瘤大小和淋巴结转移均无明显关系(P＞0.05)。
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。对于SSTR2和SSTR5阳性的A549细胞,奥曲肽紫杉醇偶联物能明显抑制肿瘤细胞的活性,并具有浓度和时间依赖性,同时能诱导细胞凋亡,其作用与紫杉醇类似;而对于SSTR2和SSTR5阴性的H157细胞,偶联物较紫杉醇表现出更低的细胞毒性和诱导凋亡能力。
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。奥曲肽紫杉醇偶联物能显著抑制耐药细胞株的活性,其作用强于紫杉醇。
紫杉醇在体外及体内作用于A549细胞后,MDR-1、MRP-1的表达均增高。而PTX-OCT作用后,其MDR-1、MRP-1的表达明显低于PTX组。2PTX-OCT在体外作用后,MDR-1、MRP-1的表达低于PTX组,但高于PTX-OCT处理组:而在体内,2PTX-OCT处理组MDR-1、MRP-1的表达与PTX-OCT组类似。BCRP的相对表达改变不明显。
结论:NSCLC组织具有较高的SSTR2、SSTR5表达率,而癌旁正常组织表达较低;并且其表达提示NSCLC预后好,生存期长;且与癌恶变程度相关,有可能作为判断NSCLC预后的指标。奥曲肽紫杉醇偶联物对SSTR2和SSTR5阳性的肿瘤细胞具有与紫杉醇相似的抗肿瘤活性;而对SSTR2和SSTR5阴性的肿瘤细胞则具有更弱的毒性;表现出一定的靶向治疗作用。奥曲肽紫杉醇偶联物能够抑制不同方式诱导的紫杉醇耐药株的活性,从而在一定程度上逆转NSCLC对紫杉醇的耐药。而且,PTX-OCT作用后,肿瘤多药耐药基因的增高低于PTX所致的多药耐药基因的升高,因此,可能会降低或延缓NSCLC耐药性的产生。总之,我们的实验结果表明,以生长抑素受体为靶点的药物在NSCLC的靶向治疗和耐药逆转及延缓耐药的产生中具有重要的应用前景。
OBJECTIVE: The clinical relevance of the somatostatin receptor subtype 2 (SSTR2) and somatostatin receptor 5 (SSTR5) is well defined in neuroendocrine tumors but their expression and role in human non-small cell lung cancer (NSCLC) is not yet well studied. We investigated the expression of SSTR2 and SSTR5 in human NSCLC and its adjacent normal tissues, and explored their correlations with clinical staging and prognosis. The somatostatin analogue octreotide was conjugated to paclitaxel and two conjugates were synthesized: PTX-OCT and 2PTX-OCT. Furthermore, targeted therapy effect of the conjugates on paclitaxel-resistant NSCLC cell lines induced by different methods was evaluated and the possible mechanisms underlying anti-paclitaxel resistance were elucidated. Also we analyzed the expression of multidrug resistance related genes of NSCLC cells after treatment with paclitaxel and its octreotide conjugates in vitro and in vivo to find out whether the conjugates had low induction of drug resistance.
METHODS: Immunohistochemical staining(S-P method) with specific antibodies was used to detect the expression of SSTR2 and SSTR5 in patients with NSCLC. The mRNA expression of somatostatin receptors (SSTRs) in human NSCLC cell line A549 and H157 cells was detected by reverse transcription-polymerase chain raction (RT-PCR). And the cell viability and apoptosis of A549 and H157 cells treated with paclitaxel and the paclitaxel-octreotide conjugates were measured by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and flow cytometry, respectively. Real-time PCR was also performed to evaluate the relative expression of multidrug related gene of A549 cells, A549 paclitaxel-resistant cells characterized by 3 different approaches, and A549 cells treated by paclitaxel and its octreotide conjugates in vitro and in vivo.
RESULTS: The positive rates of SSTR2 and SSTR5 expression were 62.7% and 61.0% repectively in patients with NSCLC, which were higher than their expression in adjacent normal tissues (13.33% and 20.00%, respectively). The expression of SSTR2 and SSTR5 was significantly correlated with TNM stage and longer survival (P<0.05), but there was no relationship between the expression of SSTR2 and SSTR5 and other clinical characteristics of patients with NSCLC (P>0.05).
The mRNA expression of 5 SSTR subtypes was all detected in A549 cells, while only mRNA expression of SSTR1 and SSTR4 was detected in H157 cells. Paclitaxel and the octreotide-paclitaxel conjugates effectively inhibited the growth of A549 cells in a concentration- and time-dependent manner.The conjugates were less cytotoxic than paclitaxel in SSTR2 and SSTR5-negative H157 cell. Three NSCLC paclitaxel-resistant cell lines A549-P、A549-PS and A549-S were established, and the resistance indexes (RI) were 6.84, 77.84 and 9.98,respectively. 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. The paclitaxel-octreotide conjugates effectively inhibited the growth of paclitaxel-resistant cells, and showed more cytotoxic effect than paclitaxel. Paclitaxel obviously induced the elevated expression of MDR-1、MRP-1 mRNAs in A549 cells and xenografted tumors, which was very higher than PTX-OCT and 2PTX-OCT treated groups.
CONCLUSION: The expression of SSTR2 and SSTR5 was high in NSCLC tissues and low in adjacent normal tissues and the high expression of SSTR2 and SSTR5 in NSCLC was correlated with good prognosis and long survival. Both paclitaxel and its octreotide conjugates effectively inhibited the growth of SSTR2 and SSTR5 positive NSCLC cells in a concentration- and time-dependent manner, while the conjugates were less cytotoxic than paclitaxel in SSTR2 and SSTR5 negative NSCLC cells, which showed a SSTRs-mediated targeted therapy effect. The octreotide-paclitaxel conjugates more effectively inhibited the growth of paclitaxel-resistant cell lines and thus partially reversed the drug resistance to paclitaxel in NSCLC. Also octreotide-paclitaxel conjugates showed a low induction of multidrug resistance compared with treatment with paclitaxel in vitro and in vivo. Our results suggested that the octreotide-paclitaxel conjugates had a significant prospect in the targeted therapy mediated by SSTRs as well as reversing paclitaxel resistance and overcoming acquired paclitaxel resistance in human NSCLC.
方法:免疫组化检测人非小细胞肺癌组织SSTR2和SSTR5的表达;采用RT-PCR从mRNA水平检测人非小细胞肺癌细胞株A549和H157 SSTRs的表达;采用MTT和流式细胞术检测奥曲肽紫杉醇偶联物对两细胞株的毒性和凋亡的影响;同时采用MTT检测偶联物能否逆转不用方式诱导建立的耐药细胞株对紫杉醇的耐药作用;流式细胞术分析耐药细胞株的周期分布,实时定量PCR检测其SSTRs和多药耐药相关基因的表达,探讨偶联物逆转耐药的可能机制;实时定量PCR检测紫杉醇及其偶联物在体外及体内作用于A549细胞后其多药耐药相关基因的表达。
结果:SSTR2和SSTR5在NSCLC组织的表达率分别为62.7%和61.0%,在癌旁组织的表达率分别为为13.33%(2/15)和20.00%(3/15)。SSTR2、SSTR5蛋白表达与NSCLC的TNM分期有密切关系(P＜0.05),其表达增高提示预后较好,生存期长;但与患者的年龄、性别、吸烟与否、病理类型、肿瘤大小和淋巴结转移均无明显关系(P＞0.05)。
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。对于SSTR2和SSTR5阳性的A549细胞,奥曲肽紫杉醇偶联物能明显抑制肿瘤细胞的活性,并具有浓度和时间依赖性,同时能诱导细胞凋亡,其作用与紫杉醇类似;而对于SSTR2和SSTR5阴性的H157细胞,偶联物较紫杉醇表现出更低的细胞毒性和诱导凋亡能力。
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。奥曲肽紫杉醇偶联物能显著抑制耐药细胞株的活性,其作用强于紫杉醇。
紫杉醇在体外及体内作用于A549细胞后,MDR-1、MRP-1的表达均增高。而PTX-OCT作用后,其MDR-1、MRP-1的表达明显低于PTX组。2PTX-OCT在体外作用后,MDR-1、MRP-1的表达低于PTX组,但高于PTX-OCT处理组:而在体内,2PTX-OCT处理组MDR-1、MRP-1的表达与PTX-OCT组类似。BCRP的相对表达改变不明显。
结论:NSCLC组织具有较高的SSTR2、SSTR5表达率,而癌旁正常组织表达较低;并且其表达提示NSCLC预后好,生存期长;且与癌恶变程度相关,有可能作为判断NSCLC预后的指标。奥曲肽紫杉醇偶联物对SSTR2和SSTR5阳性的肿瘤细胞具有与紫杉醇相似的抗肿瘤活性;而对SSTR2和SSTR5阴性的肿瘤细胞则具有更弱的毒性;表现出一定的靶向治疗作用。奥曲肽紫杉醇偶联物能够抑制不同方式诱导的紫杉醇耐药株的活性,从而在一定程度上逆转NSCLC对紫杉醇的耐药。而且,PTX-OCT作用后,肿瘤多药耐药基因的增高低于PTX所致的多药耐药基因的升高,因此,可能会降低或延缓NSCLC耐药性的产生。总之,我们的实验结果表明,以生长抑素受体为靶点的药物在NSCLC的靶向治疗和耐药逆转及延缓耐药的产生中具有重要的应用前景。
OBJECTIVE: The clinical relevance of the somatostatin receptor subtype 2 (SSTR2) and somatostatin receptor 5 (SSTR5) is well defined in neuroendocrine tumors but their expression and role in human non-small cell lung cancer (NSCLC) is not yet well studied. We investigated the expression of SSTR2 and SSTR5 in human NSCLC and its adjacent normal tissues, and explored their correlations with clinical staging and prognosis. The somatostatin analogue octreotide was conjugated to paclitaxel and two conjugates were synthesized: PTX-OCT and 2PTX-OCT. Furthermore, targeted therapy effect of the conjugates on paclitaxel-resistant NSCLC cell lines induced by different methods was evaluated and the possible mechanisms underlying anti-paclitaxel resistance were elucidated. Also we analyzed the expression of multidrug resistance related genes of NSCLC cells after treatment with paclitaxel and its octreotide conjugates in vitro and in vivo to find out whether the conjugates had low induction of drug resistance.
METHODS: Immunohistochemical staining(S-P method) with specific antibodies was used to detect the expression of SSTR2 and SSTR5 in patients with NSCLC. The mRNA expression of somatostatin receptors (SSTRs) in human NSCLC cell line A549 and H157 cells was detected by reverse transcription-polymerase chain raction (RT-PCR). And the cell viability and apoptosis of A549 and H157 cells treated with paclitaxel and the paclitaxel-octreotide conjugates were measured by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and flow cytometry, respectively. Real-time PCR was also performed to evaluate the relative expression of multidrug related gene of A549 cells, A549 paclitaxel-resistant cells characterized by 3 different approaches, and A549 cells treated by paclitaxel and its octreotide conjugates in vitro and in vivo.
RESULTS: The positive rates of SSTR2 and SSTR5 expression were 62.7% and 61.0% repectively in patients with NSCLC, which were higher than their expression in adjacent normal tissues (13.33% and 20.00%, respectively). The expression of SSTR2 and SSTR5 was significantly correlated with TNM stage and longer survival (P<0.05), but there was no relationship between the expression of SSTR2 and SSTR5 and other clinical characteristics of patients with NSCLC (P>0.05).
The mRNA expression of 5 SSTR subtypes was all detected in A549 cells, while only mRNA expression of SSTR1 and SSTR4 was detected in H157 cells. Paclitaxel and the octreotide-paclitaxel conjugates effectively inhibited the growth of A549 cells in a concentration- and time-dependent manner.The conjugates were less cytotoxic than paclitaxel in SSTR2 and SSTR5-negative H157 cell. Three NSCLC paclitaxel-resistant cell lines A549-P、A549-PS and A549-S were established, and the resistance indexes (RI) were 6.84, 77.84 and 9.98,respectively. 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. The paclitaxel-octreotide conjugates effectively inhibited the growth of paclitaxel-resistant cells, and showed more cytotoxic effect than paclitaxel. Paclitaxel obviously induced the elevated expression of MDR-1、MRP-1 mRNAs in A549 cells and xenografted tumors, which was very higher than PTX-OCT and 2PTX-OCT treated groups.
CONCLUSION: The expression of SSTR2 and SSTR5 was high in NSCLC tissues and low in adjacent normal tissues and the high expression of SSTR2 and SSTR5 in NSCLC was correlated with good prognosis and long survival. Both paclitaxel and its octreotide conjugates effectively inhibited the growth of SSTR2 and SSTR5 positive NSCLC cells in a concentration- and time-dependent manner, while the conjugates were less cytotoxic than paclitaxel in SSTR2 and SSTR5 negative NSCLC cells, which showed a SSTRs-mediated targeted therapy effect. The octreotide-paclitaxel conjugates more effectively inhibited the growth of paclitaxel-resistant cell lines and thus partially reversed the drug resistance to paclitaxel in NSCLC. Also octreotide-paclitaxel conjugates showed a low induction of multidrug resistance compared with treatment with paclitaxel in vitro and in vivo. Our results suggested that the octreotide-paclitaxel conjugates had a significant prospect in the targeted therapy mediated by SSTRs as well as reversing paclitaxel resistance and overcoming acquired paclitaxel resistance in human NSCLC.
引文
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