大环内酯类化合物逆转肿瘤细胞（MCF-7/adr）多药耐药性的研究
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摘要
恶性肿瘤是目前人类死亡的一个重要原因,化学药物治疗在肿瘤的治疗中占有非常重要的地位。但由于在临床化疗过程中肿瘤细胞产生的多药耐药(multidrug resistance, MDR),使化疗药物难以起效甚至无效。可见,成功逆转肿瘤细胞MDR直接关系到肿瘤患者的化疗效果。然而,目前所研究的逆转MDR药物,多数副作用大、效果有限,至今仍未找到一种理想的逆转药物。近年来,大环内酯类的药物应用越来越广泛,并且毒副作用小、疗效佳,可能成为一种理想的MDR逆转剂。因此,本实验选用5种大环内酯类药物研究其对肿瘤细胞人乳腺癌耐阿霉素细胞系(MCF-7/adr)在体外及裸鼠体内的逆转作用及相应机制,旨在开发一种有效的肿瘤MDR逆转药物。
首先在体外采用浓度梯度联合高浓度反复间歇诱导法构建人乳腺癌耐阿霉素细胞系(MCF-7/adr),测定耐药指数；采用MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide]方法测定逆转药物的逆转作用。其次研究试验药物的逆转MDR的机制,通过检测经药物预处理的MCF-7/adr细胞中罗丹明123和ADR积累及罗丹明123外排的变化,探讨药物能否与P-gp结合、抑制其泵出功能来逆转MCF-7/adr细胞的MDR；通过RT-PCR半定量及流式细胞仪法检测药物作用MCF-7/adr细胞后MDR 1基因和MRP 1基因及P-gp蛋白的表达。最后为进行实验药物的体内逆转MDR实验研究,我们还测定试验药物对CYP1A2 (P450酶)活性的影响及对正常人成纤维细胞及外周血单个核细胞的毒性作用；并在体外构建人乳腺癌MCF-7/adr移植瘤Balb/c裸鼠模型,选取体外逆转MDR作用最强的一种药物作用后测量裸鼠的平均生存时间和肿瘤体积。
结果表明,在体外构建的耐药细胞系耐药指数高达61倍,并检测到多拉菌素、米尔贝A4、尼莫克汀、米尔贝β14和次级米尔贝D在浓度为5umol/L时,逆转倍数分别为28.93、22.23、16.64、13.50、10.59倍,逆转作用均高于维拉帕米阳性对照组。此外,试验结果发现实验组较对照组MCF-7/adr细胞中的罗丹明123和ADR积累明显增加,而罗丹明123外排减少(P<0.05),并表现出剂量依赖与时间依赖关系,其中,疏水性最强的多拉菌素作用效果最为明显。同时,经药物逆转作用后明显降低了MDR 1基因、P-gp和MRP 1基因的表达(P<0.05)。进一步试验发现试验药物显示低浓度的试验药物对CYP1A2代谢活性无影响(P>0.05),且对正常人成纤维细胞及外周血单个核细胞的无毒剂量IC10分别为(4.545±0.876)μmol／L、(4.029±0.638)μmol／L；将多拉菌素与ADR联合应用后可显著延长荷人耐药乳腺癌细胞MCF-7/adr移植瘤裸鼠的平均生存时间,抑制实体移植瘤的增长(P<0.05)。
综上,本研究成功建立了MCF-7细胞的多药耐药细胞系,并发现5种大环内酯类药物体外可以有效地逆转肿瘤细胞的MDR,主要通过两种机制：一是与P-gp竞争性结合,抑制其泵出功能；二是降低MDR 1基因和P-gp的表达,以及MRP 1基因的表达。进一步发现多拉菌素在体内有良好的逆转MDR作用,为其它四种米尔贝类药物的体内研究提供了理论依据。试验选用的药物有可能成为安全有效的逆转肿瘤多药耐药的化疗辅助药物,为肿瘤患者的有效化疗带来新的希望。
Cancer is one of the important causes of human death at present, and chemotherapy plays a very important role in cancer treatment. But chemotherapy drugs are difficult efficacy or even invalid because the tumor cells produce multi-drug resistance (MDR) during the progress of clinical chemotherapy. Therefore, the successful reversal of MDR could improve the effects on the patients. So far the drugs reversing MDR have been researched, but they have the side effects or the limited efficacy, there is not still an ideal reversal drug. In recent years, with more and more extensive applications of macrolide drugs, and they have no toxic side effects, well efficacy and structural features, they may be an ideal MDR reversal agents. In this study, we chose the five kinds of macrolides to investigate the effects on reversing to the tumor cells resistance to adriamycin in human breast cancer cell line (MCF-7/adr) in vitro and in vivo, and the corresponding mechanisms, to develop an effective tumor MDR reversal drugs.
In vitro study, firstly, we established the MCF-7/adr cell line with increasing concentrations of adriamycin (ADR) gradient and the high concentration gradient way by repeating intermittent administration of adriamycin, then tested the resistance index, and evaluated the efficacy of doramectin, milbemycin A4, nemadectin, milbemycinβ14 and secomilbemycin D overcoming MDR of MCF-7/adr cells via MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] approach. Secondly, we detected whether the five drugs blocked drug pump function of P-gp by detected the dose of adriamycin and Rh123 since they are good P-gp substrates with an autofluorescence capacity. We also employed the RT-PCR and immunofluorescence flow cytometry to check the expressions of MDR 1 and MRP 1 mRNA and P-gp. Finally, before the experiment in vivo, we measured the effect of tested drugs on CYP1A2 (one of P450 enzymes) activity and the toxic effect on the normal human fibroblasts and peripheral blood mononuclear cells. Then we established human cancer MCF-7/adr xenograft in nude mice, and selected doramectin, the best performing drug in vitro, as experimental agent in vivo. Combining with ADR, we tested the mean surviving time (MST) of xenografts nude mice and the volume of the transplanted tumor.
The results showed that the resistance index of MCF-7/adr cell line resistant is up to 61 times in vitro. And our findings also demonstrated that 5μM doramectin, milbemycin A4, nemadectin, milbemycinβ14 and secomilbemycin D could reverse the MDR, and fold-reversal was 28.93、22.23、16.64、13.50 and 10.59, respectively, and they were better than VRP on reversing MDR. In addition, the five drugs in the experimental groups, especially doramectin with the highest hydrophobic, could concentration-dependent enhance the accumulation of intracellular adriamycin and Rh123, but did not affect that of parental MCF-7 cells (P<0.05). In the efflux assay, these compounds could inhibit the efflux of Rh123 from treated MCF-7/adr cells in a time-dependent manner. At the same time, The data showed that doramectin, milbemycin A4 and nemadectin could decrease the expressions of MDR 1 gene, MRP 1 gene and P-gp protein (P< 0.05). For the future study, our results showed that low concentrations of tested drugs had no effect on the CYP1A2 metabolic activity (P>0.05) and no obvious toxic effects can be observed on the normal human fibroblasts and peripheral blood mononuclear cells (IC 10:4.545±0.876μmol/L,4.029±0.638μmol/L). Moreover, doramectin in combination with ADR can significantly extended the mean surviving time (MST) of xenografts nude mice and inhibit the growth of transplanted tumor (P<0.05)
In summary, we successfully established MCF-7 cells in multi-drug resistant cell line, and provided abundant evidences here revealing that the five drugs could effectively reverse MDR of MCF-7/adr cells in vitro through two main mechanisms:via inhibiting the P-gp pump function and down regulating expressions of MDR1 gene and P-gp and MRP 1 gene. Among them doramectin containing sugar moiety especially appeared more effective as MDR modulator than the others, therefore, we detected its effect of reversal MDR in vivo and provided a theoretical basis for the studies of other milbemycins reversing MDR in vivo. In conclusion, the five drugs might be candidates as effective MDR reversing agents in cancer chemotherapy, and take the hope for cancer patients undergoing the chemotherapy.
首先在体外采用浓度梯度联合高浓度反复间歇诱导法构建人乳腺癌耐阿霉素细胞系(MCF-7/adr),测定耐药指数；采用MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide]方法测定逆转药物的逆转作用。其次研究试验药物的逆转MDR的机制,通过检测经药物预处理的MCF-7/adr细胞中罗丹明123和ADR积累及罗丹明123外排的变化,探讨药物能否与P-gp结合、抑制其泵出功能来逆转MCF-7/adr细胞的MDR；通过RT-PCR半定量及流式细胞仪法检测药物作用MCF-7/adr细胞后MDR 1基因和MRP 1基因及P-gp蛋白的表达。最后为进行实验药物的体内逆转MDR实验研究,我们还测定试验药物对CYP1A2 (P450酶)活性的影响及对正常人成纤维细胞及外周血单个核细胞的毒性作用；并在体外构建人乳腺癌MCF-7/adr移植瘤Balb/c裸鼠模型,选取体外逆转MDR作用最强的一种药物作用后测量裸鼠的平均生存时间和肿瘤体积。
结果表明,在体外构建的耐药细胞系耐药指数高达61倍,并检测到多拉菌素、米尔贝A4、尼莫克汀、米尔贝β14和次级米尔贝D在浓度为5umol/L时,逆转倍数分别为28.93、22.23、16.64、13.50、10.59倍,逆转作用均高于维拉帕米阳性对照组。此外,试验结果发现实验组较对照组MCF-7/adr细胞中的罗丹明123和ADR积累明显增加,而罗丹明123外排减少(P<0.05),并表现出剂量依赖与时间依赖关系,其中,疏水性最强的多拉菌素作用效果最为明显。同时,经药物逆转作用后明显降低了MDR 1基因、P-gp和MRP 1基因的表达(P<0.05)。进一步试验发现试验药物显示低浓度的试验药物对CYP1A2代谢活性无影响(P>0.05),且对正常人成纤维细胞及外周血单个核细胞的无毒剂量IC10分别为(4.545±0.876)μmol／L、(4.029±0.638)μmol／L；将多拉菌素与ADR联合应用后可显著延长荷人耐药乳腺癌细胞MCF-7/adr移植瘤裸鼠的平均生存时间,抑制实体移植瘤的增长(P<0.05)。
综上,本研究成功建立了MCF-7细胞的多药耐药细胞系,并发现5种大环内酯类药物体外可以有效地逆转肿瘤细胞的MDR,主要通过两种机制：一是与P-gp竞争性结合,抑制其泵出功能；二是降低MDR 1基因和P-gp的表达,以及MRP 1基因的表达。进一步发现多拉菌素在体内有良好的逆转MDR作用,为其它四种米尔贝类药物的体内研究提供了理论依据。试验选用的药物有可能成为安全有效的逆转肿瘤多药耐药的化疗辅助药物,为肿瘤患者的有效化疗带来新的希望。
Cancer is one of the important causes of human death at present, and chemotherapy plays a very important role in cancer treatment. But chemotherapy drugs are difficult efficacy or even invalid because the tumor cells produce multi-drug resistance (MDR) during the progress of clinical chemotherapy. Therefore, the successful reversal of MDR could improve the effects on the patients. So far the drugs reversing MDR have been researched, but they have the side effects or the limited efficacy, there is not still an ideal reversal drug. In recent years, with more and more extensive applications of macrolide drugs, and they have no toxic side effects, well efficacy and structural features, they may be an ideal MDR reversal agents. In this study, we chose the five kinds of macrolides to investigate the effects on reversing to the tumor cells resistance to adriamycin in human breast cancer cell line (MCF-7/adr) in vitro and in vivo, and the corresponding mechanisms, to develop an effective tumor MDR reversal drugs.
In vitro study, firstly, we established the MCF-7/adr cell line with increasing concentrations of adriamycin (ADR) gradient and the high concentration gradient way by repeating intermittent administration of adriamycin, then tested the resistance index, and evaluated the efficacy of doramectin, milbemycin A4, nemadectin, milbemycinβ14 and secomilbemycin D overcoming MDR of MCF-7/adr cells via MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] approach. Secondly, we detected whether the five drugs blocked drug pump function of P-gp by detected the dose of adriamycin and Rh123 since they are good P-gp substrates with an autofluorescence capacity. We also employed the RT-PCR and immunofluorescence flow cytometry to check the expressions of MDR 1 and MRP 1 mRNA and P-gp. Finally, before the experiment in vivo, we measured the effect of tested drugs on CYP1A2 (one of P450 enzymes) activity and the toxic effect on the normal human fibroblasts and peripheral blood mononuclear cells. Then we established human cancer MCF-7/adr xenograft in nude mice, and selected doramectin, the best performing drug in vitro, as experimental agent in vivo. Combining with ADR, we tested the mean surviving time (MST) of xenografts nude mice and the volume of the transplanted tumor.
The results showed that the resistance index of MCF-7/adr cell line resistant is up to 61 times in vitro. And our findings also demonstrated that 5μM doramectin, milbemycin A4, nemadectin, milbemycinβ14 and secomilbemycin D could reverse the MDR, and fold-reversal was 28.93、22.23、16.64、13.50 and 10.59, respectively, and they were better than VRP on reversing MDR. In addition, the five drugs in the experimental groups, especially doramectin with the highest hydrophobic, could concentration-dependent enhance the accumulation of intracellular adriamycin and Rh123, but did not affect that of parental MCF-7 cells (P<0.05). In the efflux assay, these compounds could inhibit the efflux of Rh123 from treated MCF-7/adr cells in a time-dependent manner. At the same time, The data showed that doramectin, milbemycin A4 and nemadectin could decrease the expressions of MDR 1 gene, MRP 1 gene and P-gp protein (P< 0.05). For the future study, our results showed that low concentrations of tested drugs had no effect on the CYP1A2 metabolic activity (P>0.05) and no obvious toxic effects can be observed on the normal human fibroblasts and peripheral blood mononuclear cells (IC 10:4.545±0.876μmol/L,4.029±0.638μmol/L). Moreover, doramectin in combination with ADR can significantly extended the mean surviving time (MST) of xenografts nude mice and inhibit the growth of transplanted tumor (P<0.05)
In summary, we successfully established MCF-7 cells in multi-drug resistant cell line, and provided abundant evidences here revealing that the five drugs could effectively reverse MDR of MCF-7/adr cells in vitro through two main mechanisms:via inhibiting the P-gp pump function and down regulating expressions of MDR1 gene and P-gp and MRP 1 gene. Among them doramectin containing sugar moiety especially appeared more effective as MDR modulator than the others, therefore, we detected its effect of reversal MDR in vivo and provided a theoretical basis for the studies of other milbemycins reversing MDR in vivo. In conclusion, the five drugs might be candidates as effective MDR reversing agents in cancer chemotherapy, and take the hope for cancer patients undergoing the chemotherapy.
引文
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Yu ST, Chen TM, Tseng SY, et al.2007. Tryptanthrin inhibits MDR1 and reverses doxorubicin resistance in breast cancer cells. Biochem Biophys Res Commun,358:79～84.
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Zheng LH, Bao YL, Wu Y, et al.2008. Cantharidin reverses multidrug resistance of human hepatoma HepG2/ADM cells via down-regulation of P-glycoprotein expression. Cancer Lett,272: 102～109.
Zhou Y, Eppenberger-Castori S, Eppenberger U.2005. The NFkappaB pathway and endocrine-resistant breast cancer. Endocr Relat Cancer,12(Suppl 1):S37.
Zhou Y, Hopper-Borge E, Shen T, et al.2009. Cepharanthine is a potent reversal agent for MRP 17(ABCC10)-mediated multidrug resistance. Biochem Pharmacol,77:993～1001.
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