盐酸千金藤碱逆转肿瘤多药耐药性的作用及其机制
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摘要
目前,临床肿瘤的化学治疗仍然是主要的治疗方法之一。但随着化疗药物的大量应用,临床肿瘤患者产生多药耐药性(multidrug resistance, MDR)越加严重,直接影响临床肿瘤病人的治疗效果,其中多药耐药基因MDR1编码的P糖蛋白(P-glycoprotein, P-gp)过度表达是MDR的重要机制之一。鉴于此,寻找肿瘤MDR逆转剂,提高肿瘤对化疗的敏感性,是医药学界当前亟待解决的问题。国内外虽然发现了一些逆转MDR的化合物,一部分已经进入了Ⅰ/Ⅱ期临床研究,但多数都由于毒副作用较大,限制了其临床应用。因此,研发低毒、高效的逆转MDR药物尤为重要。
盐酸千金藤碱(cepharanthine hydrochloride, CH)是从千金藤属植物中提取分离的一种单体化合物,经半合成而获得。本课题组前期研究证实CH逆转MDR涉及多种机制。但国内外尚无CH调控JNK信号转导通路及其体内逆转MDR作用的研究,本课题将对此进行研究,共分三部分：第一部分是在转录水平和蛋白水平研究CH对P-gp表达的信号转导通路调控的机制,为CH进一步开发提供理论和实验依据。第二部分旨在通过检测CH给药前后荷耐药肿瘤小鼠外周血CD8+细胞中P-gp活性的变化,探讨一种在动物模型中评价以P-gp为靶点的耐药逆转剂效果的方法,并考察CH在体内的肿瘤耐药逆转作用,从而为CH或者其他潜在的MDR逆转剂的研究提供科学依据。第三部分首先分析非小细胞肺癌(non-small cell lung carcinoma, NSCLC)化疗不敏感患者外周血CD56+细胞中P-gp的表达和功能变化,探讨CD56+细胞作为预测多药耐药指标的可能性,为临床提供一种检测NSCLC化疗耐药的简便方法,然后通过检测CH对外周血CD56+细胞P-gp功能的抑制作用,间接评价其对体内肿瘤细胞P-gp的抑制作用,为CH进一步应用到临床提供科学依据,同时探讨一种以临床肿瘤患者外周血CD56+细胞为替代分析指标,对P-gp抑制剂的逆转效果进行评价的方法。
第一部分盐酸千金藤碱逆转肿瘤多药耐药性的信号转导机制研究
目的：
JNK信号通路与肿瘤MDR的发生及调控MDRI基因的表达具有密切关系。本研究的目的是观察盐酸千金藤碱在人慢性粒性白血病K562耐多柔比星细胞株K562/ADR中,逆转肿瘤MDR的信号转导机制。
方法：
采用Western blot和RT-PCR法分别检测CH单用及与JNK抑制剂SP600125合用后,耐药性K562/ADR细胞中P-gp及MDR1mRNA表达的变化,考察CH对JNK通路的调控；采用Western blot法检测CH对转录因子c-Jun蛋白表达和磷酸化的影响,考察CH对c-Jun和磷酸化c-Jun的调节作用。
结果：
1、随着CH浓度的增加(5.0、10.0、20.0μM),对MDR1mRNA的抑制作用逐渐增强；随着CH(10.0μM)作用时间的延长(0、12、24、36和48h),对P-gp2MDR1mRNA的抑制作用逐渐增强；
2、CH联合JNK抑制剂SP600125后,CH对P-gp2MDR1mRNA的抑制作用减弱；
3、随着CH(10.0μM)作用时间的延长(0、6、12、24h),转录因子c-Jun的表达和磷酸化逐渐增加。
小结：
CH能够时间和浓度依赖性地下调MDR1mRNA的表达,并能够时间依赖性地下调P-gp的表达,其机制可能是活化JNK/c-Jun。
第二部分盐酸千金藤碱逆转动物体内肿瘤多药耐药性的实验研究
目的：
本研究旨在通过检测CH给药前后荷耐药肿瘤小鼠外周血CD8+细胞中P-gp活性的变化,以及CH联合临床FAP化疗方案对耐药性肿瘤生长的抑制作用,评价CH逆转体内肿瘤MDR的作用,探讨一种在动物模型中评价以P-gp为靶点的MDR逆转剂疗效的方法,从而为CH或者其他MDR逆转剂的研究提供科学依据。
方法：
采用小鼠肝癌多药耐药细胞株Hca/FAP通过腋下接种建立耐药实体型肿瘤动物模型,在该模型中研究CH在体外、体内干预后外周血CD8+细胞P-gp功能的变化。利用CD8+细胞中的罗丹明123(Rho123)蓄积作为一个替代分析指标,采用流式细胞术检测CD8+细胞内Rho123的平均荧光强度(MFI),其变化反映P-gp功能的改变。
结果：
1、给小鼠尾静脉注射0.5、1.0、2.5、5.0、7.5mg/kg的Rho123剂量后,外周血CD8+细胞中的MFl分别为2.6±0.3、3.9±0.4、8.6±0.4、16.4±±0.5、21.9±0.5,呈剂量依赖性变化；
2、体外全血中,不同浓度CH(10.0、5.0、2.5μM)或维拉帕米(VER)5.01.tM或生理盐水(NS)均分别合用0.5μg/mL Rho123后全血中CD8+细胞中的MFI依次为29.8±0.9、25.4±1.0、22.9±0.5、20.0±0.3、14.4±0.3,经统计差异具有显著性(P＜0.05),CH浓度依赖性地增加Rho123的蓄积；
3、给荷Hca/FAP肿瘤的小鼠尾静脉注射不同剂量CH(10.0、5.0、2.5mg/kg)或VER5.0mg/kg或NS,均分别联合注射2.5mg/kg Rho123后外周血CD8+细胞中的MFI依次为18.9±0.8、13.1±0.8、11.9±0.4、10.2±0.2、8.6±0.1,经统计各组之间差异具有显著性(P＜0.05),CH剂量依赖性地增加Rho123的蓄积；
4、不同浓度的CH (10.0、5.0、2.5mg/kg)联合FAP化疗方案对Hca/FAP荷瘤小鼠的肿瘤生长有不同程度的抑制作用,与FAP组相比,联用CH组的抑瘤作用增强,且抑瘤作用与CH呈剂量依赖性,10.0mg/kg CH联合FAP化疗组的抑瘤作用最强。
小结：
CH在体内对肿瘤MDR有逆转作用,CH在体内对CD8+细胞P-gp功能的抑制作用可能反映了其对体内肿瘤耐药细胞P-gp的抑制,小鼠外周血CD8+细胞可以作为评价潜在P-gp抑制剂体内逆转作用的一个替代分析指标。
第三部分盐酸千金藤碱对人外周血CD56+细胞中P糖蛋白功能的调节及CD56与肿瘤耐药的相关性研究
目的：
本研究通过分析非小细胞肺癌(NSCLC)化疗不敏感患者外周血CD56+细胞中P-gp的表达和功能变化,探讨CD56+细胞作为预测多药耐药指标的可能性,为临床提供一种检测肿瘤化疗耐药的简便方法,并以此为基础,研究CH对CD56+细胞中P-gp的抑制作用,间接评价其对体内肿瘤细胞P-gp的抑制作用,为CH将来作为MDR逆转剂进行临床疗效评价奠定基础。
方法：
选临床27例对化疗不敏感的NSCLC患者及31例初始化疗的NSCLC患者,并设正常对照组,分别抽取外周血,采用磁珠分选分离纯化CD56+细胞,采用荧光定量PCR方法检测各组CD56+细胞中MDR1、多药耐药相关蛋白1(MRP1) mRNA的变化；采用流式细胞术检测CD56+细胞在CH体外干预下P-gP功能的变化,其功能变化通过Rho123在细胞内MFI的变化表示。
结果：
1、化疗不敏感患者27例与正常对照组相比,前者外周血CD56+细胞中MDR1mRNA表达显著增高(2-10倍),MRP1mRNA表达增加1-3倍(平均约2倍),经统计均具有显著性差异(P<0.05)；而MDR1和MRP1mRNA在化疗初始对照组与正常对照组之间无显著性差异(P>0.05)；
2、化疗不敏感组、化疗初始对照组和正常对照组外周血CD56+细胞中Rho123的荧光强度分别为15.1±2.1、20.8±2.6和21.0±2.5,与化疗初始对照组31例和正常对照组相比,化疗不敏感组患者外周血CD56+细胞中P-gp的功能增加具有显著性(P<0.05),而化疗初始对照组与正常对照组之间无显著性差异；
3、化疗不敏感患者外周血CD56+细胞的P-gp功能在CH干预下,随着CH浓度的增加逐步恢复到正常水平,而化疗初始对照组患者外周血CD56+细胞的P-gp功能在CH干预下与正常对照组无统计学差异(P>0.05)。
小结：
1、NSCLC化疗不敏感患者外周血CD56+细胞中MDR1mRNA表达和P-gP功能均明显增强,提示CD56+细胞可能是诊断NSCLC化疗耐药的一个重要生物标志物,MRP1mRNA在NSCLC化疗不敏感患者外周血CD56+细胞中表达较低,以上结果为临床NSCLC耐药的诊断提供了一个简单可行的方法；
2、CH在体外人外周血中对GD56+细胞中P-gp功能的调节可能能够充分反映其对体内肿瘤细胞中P-gp的调节作用,这为潜在P-gp抑制剂的临床疗效评价提供了一个科学、可行的方法,但仍需要进一步的临床试验研究。
全文总结：
1.CH通过活化JNK/c-Jun而调节MDR1mRNA和P-gp的表达,发挥其逆转肿瘤MDR的作用。
2.耐药性实体型动物肿瘤模型结合小鼠外周血CD8+细胞中P-gp功能检测可作为P-gp抑制剂体内肿瘤耐药逆转活性评价的一个方法,CH通过抑制P-gp的功能而发挥其体内肿瘤多药耐药逆转作用。
3. NSCLC化疗不敏感患者外周血CD56+细胞中P-gp的表达和功能检测可作为诊断肺癌化疗耐药性的一个重要方法；CH在体外全血中对CD56+细胞中P-gp功能的调节可能能够充分反映其对体内肿瘤细胞中P-gp的调节作用,这为临床肿瘤MDR逆转剂的疗效评价提供了一个科学、可行的方法,但仍需要进一步的临床试验研究。
Chemotherapy is one of the main treatments for cancer in clinical currently. However, it is more and more serious that the multidrug resistance (MDR) occurred in the cancer patients as the anti-cancer drugs widely used, which affected the patients'treatment directly. The overexpression of P-glycoprotein (P-gp), encoding by multidrug resisgance gene MDR1, is one of the important mechanisms involved in MDR. For that reason, it is a problem that should be solved quickly to search MDR reversor and improve the chemotherapy sensitivity for medicine academia currently. Although foreign researchers have already found some compounds reversering MDR and some of the compounds have already been in phase Ⅱ clinical trial, most of the compounds have been limited because of its serious toxicity. Therefore, it is even more important to develop the drug reversing MDR with high efficiency and low toxicity.
Cepharanthine hydrochloride (CH), manufactured by salification from cepharanthine, which is a biscoclaurine alkaloid, extracted from Stephania cepharantha Hayata has a reversed effect involving in multi-mechanisms from our previous studies. However, there is no study for CH on regulating JNK signal transduction pathway and its MDR reversing effect in vivo in the world currently. This study is keep going on to research the reversed mechanisms of CH based on the previous studies and to evaluate the reversed effect of CH in vivo. This study includes3parts, the part one is to research the signal transduction mechanism of CH on reversing tumor multidrug resistance at transcriptional level and protein level, to provide theory and experiment bases for the further development of CH. The part two is to explore a method for evaluating the multidrug resistance reversing effect in vivo of the inhibitor with P-gp as the target point by determining the changes of P-gp activations in peripheral blood CD8+cells in the mice models bearing MDR solid tumors before and after CH administration, and to study the reversed effect of CH in vivo, thereby to provide scientific bases for researching CH and other potential P-gp inhibitors. In the part three, we first analyzed the changes of the expression and function of P-gp in the peripheral blood CD56+cells collected and separated from the selected patients with non-small cell lung cancer (NSCLC) to explore the possibility of CD56+cells as an indicator to predict the multidrug resistance of NSCLC. And then we used the CD56+cells as a surrogate indicator to determine the P-gp inhibition effect of CH in the peripheral blood CD56+cells and to evaluate indirectly the reversing effect for tumor cells in the patients, thereby to provide scientific basis for the clinical apply of CH. In the meanwhile, we want to explore a method to evaluate the the P-gp modulating effect of the P-gp reversors in clinical using the collected peripheral blood CD56+cells from the patients as a surrogate indicator.
Part one:The Signal Transduction Mechanism of Cepharanthine Hydrochloride on Reversing Tumor Multidrug Resistance
Purpose:
c-Jun NH2-terminal kinase (JNK) signal transduction pathway has tight connection with the occurrence of multidrug resistance and the regulation of MDR1mRNA expression. The purpose of the study is to determine the signal transduction mechanism of cepharanthine hydrochloride on reversing tumor multidrug resistance in K562/ADR cells.
Methods:
A western blot and a RT-PCR analysis were used to determine the effect of CH on the expression of P-glycoprotein and MDR1mRNA in K562/ADR cells when CH used alone and combined with SP600125, a JNK inhibitor, to explore the regulation effect of CH on JNK signal transduction pathway. A Western blot analysis was used to determine the effect of CH on c-Jun protein expression and phosphorylation, to explore the regulation effect of CH on c-Jun and phosphorylated c-Jun (p-c-Jun) proteins.
Results:
1. The inhibition effect of CH on MDR1mRNA increased with the concentrations of CH increased (5.0,10.0,20.0μM), and the inhibition effect of CH on P-glycoprotein and MDRl mRNA expression increased with the incubation time (0,12,24,36and48hours).
2. The inhibition effect was weakened after CH combined with SP600125.
3. The expressions of c-Jun and p-c-Jun proteins were increasing with the incubation time of CH increased (0,6,12and24hours).
Conclusions:
CH down-regulated the expressions of MDR1mRNA and P-glycoprotein in a time-and concentration-manner, the mechanism may be mediated via activating the JNK/c-Jun.
Part two:The Evaluation of the Multidrug Resistance Reversed Effect of Cepharanthine Hydrochloride in Animal Models in vivo
Purpose:
The study is to explore a method for evaluating the multidrug resistance reversing effect in vivo of the inhibitor with P-gp as the target point by determining the changes of P-gp activations in peripheral blood CD8+cells before and after CH administration and the anti-tumor effect when CH combined with FAP chemotherapy regimen in the mice models bearing MDR solid tumors, and to evaluate the reversed effect of CH in animal models in vivo, thereby to provide scientific bases for researching CH and other P-gp inhibitors.
Methods:
The mice models bearing MDR solid tumors were established by injecting Hca/FAP tumor cells subcutaneously in the right axilla of the mice, and the changes of P-gp function in the collected peripheral blood CD8+cells were studied before and after CH administration in the mice models. Using rhodamine123accumulations in CD8+cells as a surrogate indicator to study the P-gp modulating effect of CH in vivo by flow cytometry (FCM), the mean fluorescence intensities (MFI) changes of the Rho123in the CD8+cells reflect the changes of P-gp function.
Results:
1. The intravenous injection (i.v.) administration of Rho123(0.5,1.0,2.5,5.0and7.5mg/kg) in mice produced a dose-dependent fluorescence fashion in peripheral blood CD8+cells, the MFIs in peripheral blood CD8+cells were2.6±0.3,3.9±0.4,8.6±0.4,16.4±0.5and21.9±0.5, respectively;
2. The MFIs of CD8+cells in the samples treated with the vehicle,5.0μM of verapamil (VER) and2.5,5.0and10.0μM of CH were14.4±0.3,20.0±0.3,22.9±0.5,25.4±1.0and29.8±0.9, respectively. Statistical significance was observed in the different groups (P<0.05);
3. Rho123accumulations were increased after administration of either VER (positive control) or CH and presented a clear dose dependent relationship with CH (2.5,5and10mg/kg) compared with vehicle control in the mice models. The MFIs of CD8+cells in the mice administrated with CH (10.0,5.0,2.5mg/kg), VER5.0mg/kg and the vehicle were18.9±0.8,13.1±0.8,11.9±0.4,10.2±0.2and8.6±0.1, respectively. Statistical significance was observed in the different groups (P<0.05);
4. The FAP combination chemotherapy plus10.0mg/kg of CH provided the maximum antitumor activity of the treatments studied. Compared with the FAP chemotherapy group, the antitumor effect was increased in a dose-dependent manner when the FAP combined chemotherapy plus various concentrations of CH (10.0,5.0,2.5mg/kg) was used.
Conclusions:
CH has MDR reversed effect in vivo and ex vivo; the P-gp inhibition effect of CH in CD8+cells in vivo may reflect the inhibition effect for P-gp in the MDR tumor cells. Mice peripheral blood CD8+cells can be as a surrogate indicator to evaluate the reversing effect in vivo for the potential P-gp inhibitors.
Part three:The Study of P-glycoprotein Modulating Effect of Cepharanthine Hydrochloride in Human Peripheral Blood CD56+Cells and the Relationship between CD56and MDR
Purpose:
The study is to explore the possibility of CD56+cells as an indicator to predict the multidrug resistance of non-small cell lung cancer by analyzing changes of the expression and function of P-gp in the peripheral blood CD56+cells collected and separated from the selected patients with non-small cell lung cancer, thereby to provide an easy method to detect MDR for NSCLC in clinical. Based on this, the P-gp inhibition effect was evaluated indirectly in the tumor cells in vivo by studying the P-gp inhibition effect of CH in the CD56+cells ex vivo, thereby to lay the foundations for future clinical trial to evaluate its clinical P-gp modulation effect.
Methods:
Using microbead technology and a RT-qPCR methodology, we evaluated the expression levels of MDR1and MRP1mRNA in the purified CD56+cells in the27chemoresistance and31chemo-naive NSCLC patients compared with that in the healthy volunteers. Flow cytometric analysis was used to investigate the changes of P-gp function in the CD56+cells between the three cohorts after CH administration ex vivo, the changes of P-gp function was reflected by the mean fluorescence intensities (MFI) changes of the Rho123in the CD56+cells.
Results:
1. Compared with that in the healthy volunteers, all the chemoresistance blood samples revealed about twofold-tenfold elevation markedly in the purified CD56+cells for MDR1mRNA, all the chemoresistance blood samples revealed just about onefold-to-threefold changes (about average twofold) in case of MRP1mRNA. All the chemo-naive blood samples almost had no fold changes in the level of MDR1and MRP1mRNA (P>0.05);
2. The MFIs in the total gated CD56+cells were15.1±2.1,20.8±2.6and21.0±2.5for the chemoresistance patients, the chemo-naive patients and the normal healthy volunteers, respectively. Compared with that in the healthy volunteers and31chemo-naive NSCLC patients, the changes of P-gp function in CD56+cells in the chemoresistance patients has statistical significance (P<0.05). No statistical significance (P>0.05) was seen with respect to the function of P-gp between the chemo-naive and the healthy cohorts.
3. The P-gp function was returned gradually after added different concentrations of CH in the blood collected from chemoresistance patients, and there were almost no changes for the P-gp function in the chemo-naive patients compared with the normal volunteers after added the different concentrations of CH (P>0.05).
Conclusions:
1. MDR1mRNA expression and P-gp function in peripheral CD56+cells demonstrated possible clinical relevance as one of important predictive biomarkers for the identification of chemoresistance in NSCLC, while MRP1may not play a significant role in the drug resistance in NSCLC, these results will provide a simple and feasible method to diagnose and manage the chemoresistance in NSCLC patients;
2. P-glycoprotein modulating effect of CH in peripheral blood CD56+cells ex vivo may reflect its P-gp inhibition effect in the tumor cells in vivo, this will provide a scientific and feasible method to evaluate the effect of the potential P-gp inhibitors in clinical, but it need further verification in clinical.
Conclusions for full paper:
1. The mechanism of CH download-regulated the expressions of MDR1mRNA and P-gp to reverse MDR may be mediated via activating the JNK/c-Jun.
2. CH has MDR reversed effect in the animal models in vivo by inhibiting P-gp activity; the detection of P-gp function in CD8+cells in mouse model bearing MDR solid tumor may be as a surrogate indicator to evaluate the reversing effect in vivo for the potential P-gp inhibitors.
3. P-gp in peripheral CD56+cells demonstrated possible clinical relevance as one of important predictive biomarkers for the identification of chemoresistance in NSCLC, this will provide a simple and feasible method to diagnose and manage the chemoresistance in NSCLC patients. P-glycoprotein modulating effect of CH in peripheral blood CD56+cells ex vivo may reflect its P-gp inhibition effect in the tumor cells in vivo, this will provide a scientific and feasible method to evaluate the effect of the potential P-gp inhibitors in clinical, but it need further verification in clinical.
盐酸千金藤碱(cepharanthine hydrochloride, CH)是从千金藤属植物中提取分离的一种单体化合物,经半合成而获得。本课题组前期研究证实CH逆转MDR涉及多种机制。但国内外尚无CH调控JNK信号转导通路及其体内逆转MDR作用的研究,本课题将对此进行研究,共分三部分：第一部分是在转录水平和蛋白水平研究CH对P-gp表达的信号转导通路调控的机制,为CH进一步开发提供理论和实验依据。第二部分旨在通过检测CH给药前后荷耐药肿瘤小鼠外周血CD8+细胞中P-gp活性的变化,探讨一种在动物模型中评价以P-gp为靶点的耐药逆转剂效果的方法,并考察CH在体内的肿瘤耐药逆转作用,从而为CH或者其他潜在的MDR逆转剂的研究提供科学依据。第三部分首先分析非小细胞肺癌(non-small cell lung carcinoma, NSCLC)化疗不敏感患者外周血CD56+细胞中P-gp的表达和功能变化,探讨CD56+细胞作为预测多药耐药指标的可能性,为临床提供一种检测NSCLC化疗耐药的简便方法,然后通过检测CH对外周血CD56+细胞P-gp功能的抑制作用,间接评价其对体内肿瘤细胞P-gp的抑制作用,为CH进一步应用到临床提供科学依据,同时探讨一种以临床肿瘤患者外周血CD56+细胞为替代分析指标,对P-gp抑制剂的逆转效果进行评价的方法。
第一部分盐酸千金藤碱逆转肿瘤多药耐药性的信号转导机制研究
目的：
JNK信号通路与肿瘤MDR的发生及调控MDRI基因的表达具有密切关系。本研究的目的是观察盐酸千金藤碱在人慢性粒性白血病K562耐多柔比星细胞株K562/ADR中,逆转肿瘤MDR的信号转导机制。
方法：
采用Western blot和RT-PCR法分别检测CH单用及与JNK抑制剂SP600125合用后,耐药性K562/ADR细胞中P-gp及MDR1mRNA表达的变化,考察CH对JNK通路的调控；采用Western blot法检测CH对转录因子c-Jun蛋白表达和磷酸化的影响,考察CH对c-Jun和磷酸化c-Jun的调节作用。
结果：
1、随着CH浓度的增加(5.0、10.0、20.0μM),对MDR1mRNA的抑制作用逐渐增强；随着CH(10.0μM)作用时间的延长(0、12、24、36和48h),对P-gp2MDR1mRNA的抑制作用逐渐增强；
2、CH联合JNK抑制剂SP600125后,CH对P-gp2MDR1mRNA的抑制作用减弱；
3、随着CH(10.0μM)作用时间的延长(0、6、12、24h),转录因子c-Jun的表达和磷酸化逐渐增加。
小结：
CH能够时间和浓度依赖性地下调MDR1mRNA的表达,并能够时间依赖性地下调P-gp的表达,其机制可能是活化JNK/c-Jun。
第二部分盐酸千金藤碱逆转动物体内肿瘤多药耐药性的实验研究
目的：
本研究旨在通过检测CH给药前后荷耐药肿瘤小鼠外周血CD8+细胞中P-gp活性的变化,以及CH联合临床FAP化疗方案对耐药性肿瘤生长的抑制作用,评价CH逆转体内肿瘤MDR的作用,探讨一种在动物模型中评价以P-gp为靶点的MDR逆转剂疗效的方法,从而为CH或者其他MDR逆转剂的研究提供科学依据。
方法：
采用小鼠肝癌多药耐药细胞株Hca/FAP通过腋下接种建立耐药实体型肿瘤动物模型,在该模型中研究CH在体外、体内干预后外周血CD8+细胞P-gp功能的变化。利用CD8+细胞中的罗丹明123(Rho123)蓄积作为一个替代分析指标,采用流式细胞术检测CD8+细胞内Rho123的平均荧光强度(MFI),其变化反映P-gp功能的改变。
结果：
1、给小鼠尾静脉注射0.5、1.0、2.5、5.0、7.5mg/kg的Rho123剂量后,外周血CD8+细胞中的MFl分别为2.6±0.3、3.9±0.4、8.6±0.4、16.4±±0.5、21.9±0.5,呈剂量依赖性变化；
2、体外全血中,不同浓度CH(10.0、5.0、2.5μM)或维拉帕米(VER)5.01.tM或生理盐水(NS)均分别合用0.5μg/mL Rho123后全血中CD8+细胞中的MFI依次为29.8±0.9、25.4±1.0、22.9±0.5、20.0±0.3、14.4±0.3,经统计差异具有显著性(P＜0.05),CH浓度依赖性地增加Rho123的蓄积；
3、给荷Hca/FAP肿瘤的小鼠尾静脉注射不同剂量CH(10.0、5.0、2.5mg/kg)或VER5.0mg/kg或NS,均分别联合注射2.5mg/kg Rho123后外周血CD8+细胞中的MFI依次为18.9±0.8、13.1±0.8、11.9±0.4、10.2±0.2、8.6±0.1,经统计各组之间差异具有显著性(P＜0.05),CH剂量依赖性地增加Rho123的蓄积；
4、不同浓度的CH (10.0、5.0、2.5mg/kg)联合FAP化疗方案对Hca/FAP荷瘤小鼠的肿瘤生长有不同程度的抑制作用,与FAP组相比,联用CH组的抑瘤作用增强,且抑瘤作用与CH呈剂量依赖性,10.0mg/kg CH联合FAP化疗组的抑瘤作用最强。
小结：
CH在体内对肿瘤MDR有逆转作用,CH在体内对CD8+细胞P-gp功能的抑制作用可能反映了其对体内肿瘤耐药细胞P-gp的抑制,小鼠外周血CD8+细胞可以作为评价潜在P-gp抑制剂体内逆转作用的一个替代分析指标。
第三部分盐酸千金藤碱对人外周血CD56+细胞中P糖蛋白功能的调节及CD56与肿瘤耐药的相关性研究
目的：
本研究通过分析非小细胞肺癌(NSCLC)化疗不敏感患者外周血CD56+细胞中P-gp的表达和功能变化,探讨CD56+细胞作为预测多药耐药指标的可能性,为临床提供一种检测肿瘤化疗耐药的简便方法,并以此为基础,研究CH对CD56+细胞中P-gp的抑制作用,间接评价其对体内肿瘤细胞P-gp的抑制作用,为CH将来作为MDR逆转剂进行临床疗效评价奠定基础。
方法：
选临床27例对化疗不敏感的NSCLC患者及31例初始化疗的NSCLC患者,并设正常对照组,分别抽取外周血,采用磁珠分选分离纯化CD56+细胞,采用荧光定量PCR方法检测各组CD56+细胞中MDR1、多药耐药相关蛋白1(MRP1) mRNA的变化；采用流式细胞术检测CD56+细胞在CH体外干预下P-gP功能的变化,其功能变化通过Rho123在细胞内MFI的变化表示。
结果：
1、化疗不敏感患者27例与正常对照组相比,前者外周血CD56+细胞中MDR1mRNA表达显著增高(2-10倍),MRP1mRNA表达增加1-3倍(平均约2倍),经统计均具有显著性差异(P<0.05)；而MDR1和MRP1mRNA在化疗初始对照组与正常对照组之间无显著性差异(P>0.05)；
2、化疗不敏感组、化疗初始对照组和正常对照组外周血CD56+细胞中Rho123的荧光强度分别为15.1±2.1、20.8±2.6和21.0±2.5,与化疗初始对照组31例和正常对照组相比,化疗不敏感组患者外周血CD56+细胞中P-gp的功能增加具有显著性(P<0.05),而化疗初始对照组与正常对照组之间无显著性差异；
3、化疗不敏感患者外周血CD56+细胞的P-gp功能在CH干预下,随着CH浓度的增加逐步恢复到正常水平,而化疗初始对照组患者外周血CD56+细胞的P-gp功能在CH干预下与正常对照组无统计学差异(P>0.05)。
小结：
1、NSCLC化疗不敏感患者外周血CD56+细胞中MDR1mRNA表达和P-gP功能均明显增强,提示CD56+细胞可能是诊断NSCLC化疗耐药的一个重要生物标志物,MRP1mRNA在NSCLC化疗不敏感患者外周血CD56+细胞中表达较低,以上结果为临床NSCLC耐药的诊断提供了一个简单可行的方法；
2、CH在体外人外周血中对GD56+细胞中P-gp功能的调节可能能够充分反映其对体内肿瘤细胞中P-gp的调节作用,这为潜在P-gp抑制剂的临床疗效评价提供了一个科学、可行的方法,但仍需要进一步的临床试验研究。
全文总结：
1.CH通过活化JNK/c-Jun而调节MDR1mRNA和P-gp的表达,发挥其逆转肿瘤MDR的作用。
2.耐药性实体型动物肿瘤模型结合小鼠外周血CD8+细胞中P-gp功能检测可作为P-gp抑制剂体内肿瘤耐药逆转活性评价的一个方法,CH通过抑制P-gp的功能而发挥其体内肿瘤多药耐药逆转作用。
3. NSCLC化疗不敏感患者外周血CD56+细胞中P-gp的表达和功能检测可作为诊断肺癌化疗耐药性的一个重要方法；CH在体外全血中对CD56+细胞中P-gp功能的调节可能能够充分反映其对体内肿瘤细胞中P-gp的调节作用,这为临床肿瘤MDR逆转剂的疗效评价提供了一个科学、可行的方法,但仍需要进一步的临床试验研究。
Chemotherapy is one of the main treatments for cancer in clinical currently. However, it is more and more serious that the multidrug resistance (MDR) occurred in the cancer patients as the anti-cancer drugs widely used, which affected the patients'treatment directly. The overexpression of P-glycoprotein (P-gp), encoding by multidrug resisgance gene MDR1, is one of the important mechanisms involved in MDR. For that reason, it is a problem that should be solved quickly to search MDR reversor and improve the chemotherapy sensitivity for medicine academia currently. Although foreign researchers have already found some compounds reversering MDR and some of the compounds have already been in phase Ⅱ clinical trial, most of the compounds have been limited because of its serious toxicity. Therefore, it is even more important to develop the drug reversing MDR with high efficiency and low toxicity.
Cepharanthine hydrochloride (CH), manufactured by salification from cepharanthine, which is a biscoclaurine alkaloid, extracted from Stephania cepharantha Hayata has a reversed effect involving in multi-mechanisms from our previous studies. However, there is no study for CH on regulating JNK signal transduction pathway and its MDR reversing effect in vivo in the world currently. This study is keep going on to research the reversed mechanisms of CH based on the previous studies and to evaluate the reversed effect of CH in vivo. This study includes3parts, the part one is to research the signal transduction mechanism of CH on reversing tumor multidrug resistance at transcriptional level and protein level, to provide theory and experiment bases for the further development of CH. The part two is to explore a method for evaluating the multidrug resistance reversing effect in vivo of the inhibitor with P-gp as the target point by determining the changes of P-gp activations in peripheral blood CD8+cells in the mice models bearing MDR solid tumors before and after CH administration, and to study the reversed effect of CH in vivo, thereby to provide scientific bases for researching CH and other potential P-gp inhibitors. In the part three, we first analyzed the changes of the expression and function of P-gp in the peripheral blood CD56+cells collected and separated from the selected patients with non-small cell lung cancer (NSCLC) to explore the possibility of CD56+cells as an indicator to predict the multidrug resistance of NSCLC. And then we used the CD56+cells as a surrogate indicator to determine the P-gp inhibition effect of CH in the peripheral blood CD56+cells and to evaluate indirectly the reversing effect for tumor cells in the patients, thereby to provide scientific basis for the clinical apply of CH. In the meanwhile, we want to explore a method to evaluate the the P-gp modulating effect of the P-gp reversors in clinical using the collected peripheral blood CD56+cells from the patients as a surrogate indicator.
Part one:The Signal Transduction Mechanism of Cepharanthine Hydrochloride on Reversing Tumor Multidrug Resistance
Purpose:
c-Jun NH2-terminal kinase (JNK) signal transduction pathway has tight connection with the occurrence of multidrug resistance and the regulation of MDR1mRNA expression. The purpose of the study is to determine the signal transduction mechanism of cepharanthine hydrochloride on reversing tumor multidrug resistance in K562/ADR cells.
Methods:
A western blot and a RT-PCR analysis were used to determine the effect of CH on the expression of P-glycoprotein and MDR1mRNA in K562/ADR cells when CH used alone and combined with SP600125, a JNK inhibitor, to explore the regulation effect of CH on JNK signal transduction pathway. A Western blot analysis was used to determine the effect of CH on c-Jun protein expression and phosphorylation, to explore the regulation effect of CH on c-Jun and phosphorylated c-Jun (p-c-Jun) proteins.
Results:
1. The inhibition effect of CH on MDR1mRNA increased with the concentrations of CH increased (5.0,10.0,20.0μM), and the inhibition effect of CH on P-glycoprotein and MDRl mRNA expression increased with the incubation time (0,12,24,36and48hours).
2. The inhibition effect was weakened after CH combined with SP600125.
3. The expressions of c-Jun and p-c-Jun proteins were increasing with the incubation time of CH increased (0,6,12and24hours).
Conclusions:
CH down-regulated the expressions of MDR1mRNA and P-glycoprotein in a time-and concentration-manner, the mechanism may be mediated via activating the JNK/c-Jun.
Part two:The Evaluation of the Multidrug Resistance Reversed Effect of Cepharanthine Hydrochloride in Animal Models in vivo
Purpose:
The study is to explore a method for evaluating the multidrug resistance reversing effect in vivo of the inhibitor with P-gp as the target point by determining the changes of P-gp activations in peripheral blood CD8+cells before and after CH administration and the anti-tumor effect when CH combined with FAP chemotherapy regimen in the mice models bearing MDR solid tumors, and to evaluate the reversed effect of CH in animal models in vivo, thereby to provide scientific bases for researching CH and other P-gp inhibitors.
Methods:
The mice models bearing MDR solid tumors were established by injecting Hca/FAP tumor cells subcutaneously in the right axilla of the mice, and the changes of P-gp function in the collected peripheral blood CD8+cells were studied before and after CH administration in the mice models. Using rhodamine123accumulations in CD8+cells as a surrogate indicator to study the P-gp modulating effect of CH in vivo by flow cytometry (FCM), the mean fluorescence intensities (MFI) changes of the Rho123in the CD8+cells reflect the changes of P-gp function.
Results:
1. The intravenous injection (i.v.) administration of Rho123(0.5,1.0,2.5,5.0and7.5mg/kg) in mice produced a dose-dependent fluorescence fashion in peripheral blood CD8+cells, the MFIs in peripheral blood CD8+cells were2.6±0.3,3.9±0.4,8.6±0.4,16.4±0.5and21.9±0.5, respectively;
2. The MFIs of CD8+cells in the samples treated with the vehicle,5.0μM of verapamil (VER) and2.5,5.0and10.0μM of CH were14.4±0.3,20.0±0.3,22.9±0.5,25.4±1.0and29.8±0.9, respectively. Statistical significance was observed in the different groups (P<0.05);
3. Rho123accumulations were increased after administration of either VER (positive control) or CH and presented a clear dose dependent relationship with CH (2.5,5and10mg/kg) compared with vehicle control in the mice models. The MFIs of CD8+cells in the mice administrated with CH (10.0,5.0,2.5mg/kg), VER5.0mg/kg and the vehicle were18.9±0.8,13.1±0.8,11.9±0.4,10.2±0.2and8.6±0.1, respectively. Statistical significance was observed in the different groups (P<0.05);
4. The FAP combination chemotherapy plus10.0mg/kg of CH provided the maximum antitumor activity of the treatments studied. Compared with the FAP chemotherapy group, the antitumor effect was increased in a dose-dependent manner when the FAP combined chemotherapy plus various concentrations of CH (10.0,5.0,2.5mg/kg) was used.
Conclusions:
CH has MDR reversed effect in vivo and ex vivo; the P-gp inhibition effect of CH in CD8+cells in vivo may reflect the inhibition effect for P-gp in the MDR tumor cells. Mice peripheral blood CD8+cells can be as a surrogate indicator to evaluate the reversing effect in vivo for the potential P-gp inhibitors.
Part three:The Study of P-glycoprotein Modulating Effect of Cepharanthine Hydrochloride in Human Peripheral Blood CD56+Cells and the Relationship between CD56and MDR
Purpose:
The study is to explore the possibility of CD56+cells as an indicator to predict the multidrug resistance of non-small cell lung cancer by analyzing changes of the expression and function of P-gp in the peripheral blood CD56+cells collected and separated from the selected patients with non-small cell lung cancer, thereby to provide an easy method to detect MDR for NSCLC in clinical. Based on this, the P-gp inhibition effect was evaluated indirectly in the tumor cells in vivo by studying the P-gp inhibition effect of CH in the CD56+cells ex vivo, thereby to lay the foundations for future clinical trial to evaluate its clinical P-gp modulation effect.
Methods:
Using microbead technology and a RT-qPCR methodology, we evaluated the expression levels of MDR1and MRP1mRNA in the purified CD56+cells in the27chemoresistance and31chemo-naive NSCLC patients compared with that in the healthy volunteers. Flow cytometric analysis was used to investigate the changes of P-gp function in the CD56+cells between the three cohorts after CH administration ex vivo, the changes of P-gp function was reflected by the mean fluorescence intensities (MFI) changes of the Rho123in the CD56+cells.
Results:
1. Compared with that in the healthy volunteers, all the chemoresistance blood samples revealed about twofold-tenfold elevation markedly in the purified CD56+cells for MDR1mRNA, all the chemoresistance blood samples revealed just about onefold-to-threefold changes (about average twofold) in case of MRP1mRNA. All the chemo-naive blood samples almost had no fold changes in the level of MDR1and MRP1mRNA (P>0.05);
2. The MFIs in the total gated CD56+cells were15.1±2.1,20.8±2.6and21.0±2.5for the chemoresistance patients, the chemo-naive patients and the normal healthy volunteers, respectively. Compared with that in the healthy volunteers and31chemo-naive NSCLC patients, the changes of P-gp function in CD56+cells in the chemoresistance patients has statistical significance (P<0.05). No statistical significance (P>0.05) was seen with respect to the function of P-gp between the chemo-naive and the healthy cohorts.
3. The P-gp function was returned gradually after added different concentrations of CH in the blood collected from chemoresistance patients, and there were almost no changes for the P-gp function in the chemo-naive patients compared with the normal volunteers after added the different concentrations of CH (P>0.05).
Conclusions:
1. MDR1mRNA expression and P-gp function in peripheral CD56+cells demonstrated possible clinical relevance as one of important predictive biomarkers for the identification of chemoresistance in NSCLC, while MRP1may not play a significant role in the drug resistance in NSCLC, these results will provide a simple and feasible method to diagnose and manage the chemoresistance in NSCLC patients;
2. P-glycoprotein modulating effect of CH in peripheral blood CD56+cells ex vivo may reflect its P-gp inhibition effect in the tumor cells in vivo, this will provide a scientific and feasible method to evaluate the effect of the potential P-gp inhibitors in clinical, but it need further verification in clinical.
Conclusions for full paper:
1. The mechanism of CH download-regulated the expressions of MDR1mRNA and P-gp to reverse MDR may be mediated via activating the JNK/c-Jun.
2. CH has MDR reversed effect in the animal models in vivo by inhibiting P-gp activity; the detection of P-gp function in CD8+cells in mouse model bearing MDR solid tumor may be as a surrogate indicator to evaluate the reversing effect in vivo for the potential P-gp inhibitors.
3. P-gp in peripheral CD56+cells demonstrated possible clinical relevance as one of important predictive biomarkers for the identification of chemoresistance in NSCLC, this will provide a simple and feasible method to diagnose and manage the chemoresistance in NSCLC patients. P-glycoprotein modulating effect of CH in peripheral blood CD56+cells ex vivo may reflect its P-gp inhibition effect in the tumor cells in vivo, this will provide a scientific and feasible method to evaluate the effect of the potential P-gp inhibitors in clinical, but it need further verification in clinical.
引文
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