夏枯草对肿瘤细胞多药耐药基因表达影响的研究
摘要
背景和目的
根据世界卫生组织(WHO)的报告,2000年全球恶性肿瘤死亡例数已经超过700万,占全部死亡人数的12%,在发展中国家占人口总数的9%,在发达国家占21%。我国是发展中国家,恶性肿瘤占居民死亡原因的19%,居常见死亡原因的首位。目前,化学药物治疗是治疗人体恶性肿瘤的重要手段,尽管不断有新的化疗药物和化疗方案推出,但肿瘤细胞对多种化疗药物产生的多药耐药性仍是化疗失败的主要原因之一,也是肿瘤治疗的一大难题。
多药耐药性(multidrug resistance,MDR)是指肿瘤细胞对一种抗肿瘤药物产生抗药性的同时,对结构和作用机制不同的抗癌药物产生交叉耐药性。MDR形成的机理非常复杂,肿瘤细胞可以通过不同途径导致MDR产生,而一种MDR细胞可以同时存在多种抗药性机制。根据美国恶性肿瘤协会估计,每年恶性肿瘤患者约49万例死亡,其中90%以上患者的死亡受到耐药在不同程度上的影响。因此,探求MDR现象产生的机制及寻求肿瘤多药耐药逆转剂或逆转方法已经成为国内外的研究的热点。
近年来,研究比较多的多药耐药逆转剂维拉帕米(verapamil,VER)等及反义RNA技术、反义寡核苷酸技术、核酶技术以及基因敲除术为主导的基因逆转方法或因大剂量造成的明显的毒副作用,或因高成本、高技术难度,都使他们在临床应用上受到限制。作为我国国粹的中草药,治疗肿瘤的历史十分久远,因其具备“廉价、毒性小、安全范围大、广谱性强、作用靶点多”等作为耐药肿瘤逆转剂的诸多优势,加之很多中草药复方或单体本身就有一定的抗肿瘤作用,所以在耐药性肿瘤逆转剂的研究中,受到越来越广泛的关注。近年来文献报告已经证实,中药具有逆转MDR的生物活性成分:如黄酮类化合物、汉防已甲素、人参皂甙、雄黄、榄香烯以及某些中药复方都具有体外逆转MDR的作用。因此,中药在筛选MDR逆转剂的研究中具有很广阔的应用前景。
夏枯草(Prunella vulgaris,PV)为唇形科PV属植物PV的干燥成熟果穗,具有清火明目、软坚散结之功效,其对多种肿瘤细胞有抑制增殖及诱导凋亡的作用,但PV在逆转多药耐药方面的研究鲜有报道。中国医科大学2006届硕士研究生周新颖的研究证实了PV可部分逆转乳腺癌细胞耐药,但对人Burkitt淋巴瘤细胞株Raji、人乳腺癌细胞株MDA-MB-435s及人肝癌细胞SMMC-7721耐药的逆转尚未见报道。
本研究运用逆转录多聚酶链式反应(RT-PCR)技术观察非毒性细胞剂量下不同浓度的PV对Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞多药耐药基因表达的影响,探讨可能存在的耐药逆转机制,以期找到具有临床应用前景的耐药逆转治疗药物。
方法
1 MTT法测定阿霉素(ADM)单用和PV与不同浓度梯度ADM联合应用对Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞的半数抑制率(IC_(50))。
2运用逆转录多聚酶链式反应(RT-PCR)检测非细胞毒性剂量下不同浓度的PV对Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞mdr1基因表达水平的影响。
结果
1 PV对Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞的抑制作用具有剂量依赖性。通过剂量效应曲线可确定PV的非细胞毒性剂量(生长率＞95%)分别为10.0μg/ml、20.0μg/ml、30.0μg/ml,PV对三种肿瘤细胞的半数抑制浓度IC_(50)分别为31.67±0.89μg/ml、63.03±1.22μg/ml、81.45±2.16μg/ml。ADM对三种肿瘤细胞的IC_(50)分别为1.28±0.66μg/ml、1.87±0.85μg/ml、2.39±1.58μg/ml,选用非细胞毒性剂量浓度的PV与不同浓度的ADM联合应用,其对三种肿瘤细胞的IC_(50)分别下降为0.77±0.35μg/ml、1.38±0.84μg/ml、1.96±1.19μg/ml。从结果中可以看出,PV与ADM共同作用于肿瘤细胞时,ADM的IC_(50)值与ADM单独作用于肿瘤细胞时相比结果具有显著性差异(P＜0.05)
2 PV对肿瘤细胞多药耐药基因mdr1基因的影响,从电泳图上可以看出,Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞均有mdr1基因的表达,且SMMC-7721细胞表达最强,MDA-MB-435s细胞表达居中,Raji细胞表达最弱,这与临床上三种肿瘤的耐药性程度相一致。并且经过非毒性细胞剂量下不同浓度的PV处理的Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞的mdr1基因的表达要比对照组细胞的表达弱;随着PV剂量的增加,对肿瘤细胞的多药耐药基因mdr1基因的表达下调作用越明显(P＜0.05)。
结论
1 PV能抑制Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞的增殖,抑制作用呈明显的剂量依赖性。
2 PV可逆转Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞对ADM的耐药性。
3 Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞存在原发多药耐药性,mdr1基因的过表达可能是三种肿瘤细胞MDR形成的分子基础之一。
4在非细胞毒性剂量下不同浓度的PV通过调节mdr1基因的表达水平逆转或部分逆转肿瘤细胞的原发耐药,且逆转作用有剂量依赖性。
Background and Objective
According to the report of WHO,the year 2000 saw that malignancynant tumor death cases reached a startling point of 7 million around the world,which constituted an average12%of all the death cases with the 9%in developing countries and 21%in developed countries.As a developing country,China's malignancynant tumor death cases has,among all the causes,a 19%as its percentage.At present,chemotherapy is still the major means to treat malignancynant tumor patients.Athough new chemotherapy drugs and new programs have been used in the clinical,MDR is the major cause leading to the failure of tumor chemicaltherapy,and is also the major problem in tumor theatment.
Multidrug resistance(MDR) here means that the tumor cells develop cross tolerance against different drugs with different structure and mechanism of action when they begin to resist one drug.The formative mechanism of drug resistance is very complicated and tumor cells could have different ways to develop MDR,and one kind of MDR cells could have many kinds of resistance mechanisms at the same time. Based on the investigation data from the society of malignancynant tumor USA,90% of the 49 million death cases of malignancy experienced the drug resistance in different levels.Therefore,to explore the mechanism of the emerging of MDR and seek the reversal agent and method against the multidrug resistance has been becoming a hot researching issue all over the world.
In recent years,verapamil(VER),frequently studied reversal agent of drug resistance,and technology of antisense RNA,antisense oligonucleotide,ribozyme and gene knock-out thechnique backed gene reversion method all have been limited in the clinical application for the reason of toxical side effect,high cost or high degree of difficulty.Promisingly,as the our national treatures,chinese herb medicine has a long history of curing the cancer,with its merits of "low cost,little toxicity,big safety margin,strong broad spectrum and more effective target points" to be a reveral agent, which pulling more and more attentions in the researching of MDR.Records and reports have proved that herb medicine has the biological active constitutent,and flavonoids,tetrandrine,peimine,panaxoside,arsenic disulfide,elemene and other compound herb recipe also has the potency to reverse the MDR effect in vitro,which indicates all the better that herb medicine has a potential clinical application and value of exploitation,and thus deserving our deeper research.
Prunella vulgaris here refers to the dry ripe ear of brunellae cum fructu, belonging to labiatae and Prunella,which has the effectiveness of eyesight improving and endogenous fire clearing,detumescence and stagnation eliminating,this will help to restrain the proliferation of many kinds of tumor cells and to induce apoptosis, however,it is rarely reported about the researching on its reversal effect of multidrug resistance.Zhou Xinying,an graduate student from China medical university,had done some some research and proved that PV can partly reverse the drug fast of breast cancer tumor cells,but similar report has not yet been seen on the research about reversal effect on Raji cells,MDA-MB-435s cells and SMMC-7721 cells.
This research is aimed to use the RT-PCR technology and observe the effect on genetic expression of multidrug resistance in Raji cells,MDA-MB-435s cells and SMMC-7721 cells under different concentrations of PV,and in this way,to approach the mechanism of MDR with the expectation to find the potential drug fast reversal medicine with clinical application prospect.
METHODS
1 The half inhibitory rate(IC_(50)) of Raji cells、MDA-MB-435s cells and SMMC-7721 cells treated with ADM,and ADM in combination with PV were examined by MTT assay,respectively.
2 The effects of different concentrations of Prunella vulgaris on expression of mdr1 gene of Raji cells、MDA-MB-435scells and SMMC-7721 cells were detected with reverse transcriptase polymerase chain reaction(RT-PCR).
RESULTS
1 PV cytotoxicity detection,the depressant effects on Raji cells,MDA-MB-435s cells and SMMC-7721 cells bear a dose-concentration dependence.Through the dose effect curve,non-cytotoxicity dose(growth rate＞95%) could be determined as 10.0μg/ml,20μg/ml and 30μg/ml.The IC_(50) of three tumor cells dealed with PV were 31.67±0.89μg/ml、63.03±1.22μg/ml、81.45±2.16μg/ml respectively.The IC_(50) of three tumor cells dealed with ADM were 1.28±0.66μg/ml、1.87±0.85μg/ml、2.39±1.58μg/ml.We choose the PV of non-cytotoxicity dose combinedwith ADM at its correspondingly different levels of concentrations.The experimental results show that values of IC50 have significant difference(P＜0.05) between the conditions when ADM was solely used against the tumor cells and used with the combination of Prunella vulgaris.
2 The effects of Prunella vulgaris on expression mdr1 gene of tumor cells,from the rusult of study,we can see Raji cells,MDA-MB-435s cells and SMMC-7721 cells exprssion mdr1 gene,the mdr1 gene expression of SMMC-7721 cells were strongest, the mdr1 gene expression of were weakest,which were in line with the degree of resistance of three tumor cells in the clinical.Different concentrations of PV could weaken the expression level of mdr1 gene of Raji cells、MDA-MB-435s cells and SMMC-7721 cells,and with the concentration increasing,the down regulation of expression were more obvious(P＜0.05).
CONCLUSION
1 PV can inhibit Raji cells,MDA-MB-435s cells and SMMC-7721 cells proliferation,and the inhibition were dose-dependent.
2 PV is able to partly reverse the ADM-resistance in Raji cells,MDA-MB-435s cells and SMMC-7721 cells.
3 Three tumor cells have been existed primary multidrug resistance,mdr1 gene over-expression of tumor cells may be the formation of the molecular basis of MDR
4 Different concentrations of PV which under the non-cytotoxic dose could reverse or partly reverse the multidrug resistance by way of weaken the expression level of mdr1 gene.
根据世界卫生组织(WHO)的报告,2000年全球恶性肿瘤死亡例数已经超过700万,占全部死亡人数的12%,在发展中国家占人口总数的9%,在发达国家占21%。我国是发展中国家,恶性肿瘤占居民死亡原因的19%,居常见死亡原因的首位。目前,化学药物治疗是治疗人体恶性肿瘤的重要手段,尽管不断有新的化疗药物和化疗方案推出,但肿瘤细胞对多种化疗药物产生的多药耐药性仍是化疗失败的主要原因之一,也是肿瘤治疗的一大难题。
多药耐药性(multidrug resistance,MDR)是指肿瘤细胞对一种抗肿瘤药物产生抗药性的同时,对结构和作用机制不同的抗癌药物产生交叉耐药性。MDR形成的机理非常复杂,肿瘤细胞可以通过不同途径导致MDR产生,而一种MDR细胞可以同时存在多种抗药性机制。根据美国恶性肿瘤协会估计,每年恶性肿瘤患者约49万例死亡,其中90%以上患者的死亡受到耐药在不同程度上的影响。因此,探求MDR现象产生的机制及寻求肿瘤多药耐药逆转剂或逆转方法已经成为国内外的研究的热点。
近年来,研究比较多的多药耐药逆转剂维拉帕米(verapamil,VER)等及反义RNA技术、反义寡核苷酸技术、核酶技术以及基因敲除术为主导的基因逆转方法或因大剂量造成的明显的毒副作用,或因高成本、高技术难度,都使他们在临床应用上受到限制。作为我国国粹的中草药,治疗肿瘤的历史十分久远,因其具备“廉价、毒性小、安全范围大、广谱性强、作用靶点多”等作为耐药肿瘤逆转剂的诸多优势,加之很多中草药复方或单体本身就有一定的抗肿瘤作用,所以在耐药性肿瘤逆转剂的研究中,受到越来越广泛的关注。近年来文献报告已经证实,中药具有逆转MDR的生物活性成分:如黄酮类化合物、汉防已甲素、人参皂甙、雄黄、榄香烯以及某些中药复方都具有体外逆转MDR的作用。因此,中药在筛选MDR逆转剂的研究中具有很广阔的应用前景。
夏枯草(Prunella vulgaris,PV)为唇形科PV属植物PV的干燥成熟果穗,具有清火明目、软坚散结之功效,其对多种肿瘤细胞有抑制增殖及诱导凋亡的作用,但PV在逆转多药耐药方面的研究鲜有报道。中国医科大学2006届硕士研究生周新颖的研究证实了PV可部分逆转乳腺癌细胞耐药,但对人Burkitt淋巴瘤细胞株Raji、人乳腺癌细胞株MDA-MB-435s及人肝癌细胞SMMC-7721耐药的逆转尚未见报道。
本研究运用逆转录多聚酶链式反应(RT-PCR)技术观察非毒性细胞剂量下不同浓度的PV对Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞多药耐药基因表达的影响,探讨可能存在的耐药逆转机制,以期找到具有临床应用前景的耐药逆转治疗药物。
方法
1 MTT法测定阿霉素(ADM)单用和PV与不同浓度梯度ADM联合应用对Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞的半数抑制率(IC_(50))。
2运用逆转录多聚酶链式反应(RT-PCR)检测非细胞毒性剂量下不同浓度的PV对Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞mdr1基因表达水平的影响。
结果
1 PV对Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞的抑制作用具有剂量依赖性。通过剂量效应曲线可确定PV的非细胞毒性剂量(生长率＞95%)分别为10.0μg/ml、20.0μg/ml、30.0μg/ml,PV对三种肿瘤细胞的半数抑制浓度IC_(50)分别为31.67±0.89μg/ml、63.03±1.22μg/ml、81.45±2.16μg/ml。ADM对三种肿瘤细胞的IC_(50)分别为1.28±0.66μg/ml、1.87±0.85μg/ml、2.39±1.58μg/ml,选用非细胞毒性剂量浓度的PV与不同浓度的ADM联合应用,其对三种肿瘤细胞的IC_(50)分别下降为0.77±0.35μg/ml、1.38±0.84μg/ml、1.96±1.19μg/ml。从结果中可以看出,PV与ADM共同作用于肿瘤细胞时,ADM的IC_(50)值与ADM单独作用于肿瘤细胞时相比结果具有显著性差异(P＜0.05)
2 PV对肿瘤细胞多药耐药基因mdr1基因的影响,从电泳图上可以看出,Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞均有mdr1基因的表达,且SMMC-7721细胞表达最强,MDA-MB-435s细胞表达居中,Raji细胞表达最弱,这与临床上三种肿瘤的耐药性程度相一致。并且经过非毒性细胞剂量下不同浓度的PV处理的Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞的mdr1基因的表达要比对照组细胞的表达弱;随着PV剂量的增加,对肿瘤细胞的多药耐药基因mdr1基因的表达下调作用越明显(P＜0.05)。
结论
1 PV能抑制Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞的增殖,抑制作用呈明显的剂量依赖性。
2 PV可逆转Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞对ADM的耐药性。
3 Raji细胞、MDA-MB-435s细胞和SMMC-7721细胞存在原发多药耐药性,mdr1基因的过表达可能是三种肿瘤细胞MDR形成的分子基础之一。
4在非细胞毒性剂量下不同浓度的PV通过调节mdr1基因的表达水平逆转或部分逆转肿瘤细胞的原发耐药,且逆转作用有剂量依赖性。
Background and Objective
According to the report of WHO,the year 2000 saw that malignancynant tumor death cases reached a startling point of 7 million around the world,which constituted an average12%of all the death cases with the 9%in developing countries and 21%in developed countries.As a developing country,China's malignancynant tumor death cases has,among all the causes,a 19%as its percentage.At present,chemotherapy is still the major means to treat malignancynant tumor patients.Athough new chemotherapy drugs and new programs have been used in the clinical,MDR is the major cause leading to the failure of tumor chemicaltherapy,and is also the major problem in tumor theatment.
Multidrug resistance(MDR) here means that the tumor cells develop cross tolerance against different drugs with different structure and mechanism of action when they begin to resist one drug.The formative mechanism of drug resistance is very complicated and tumor cells could have different ways to develop MDR,and one kind of MDR cells could have many kinds of resistance mechanisms at the same time. Based on the investigation data from the society of malignancynant tumor USA,90% of the 49 million death cases of malignancy experienced the drug resistance in different levels.Therefore,to explore the mechanism of the emerging of MDR and seek the reversal agent and method against the multidrug resistance has been becoming a hot researching issue all over the world.
In recent years,verapamil(VER),frequently studied reversal agent of drug resistance,and technology of antisense RNA,antisense oligonucleotide,ribozyme and gene knock-out thechnique backed gene reversion method all have been limited in the clinical application for the reason of toxical side effect,high cost or high degree of difficulty.Promisingly,as the our national treatures,chinese herb medicine has a long history of curing the cancer,with its merits of "low cost,little toxicity,big safety margin,strong broad spectrum and more effective target points" to be a reveral agent, which pulling more and more attentions in the researching of MDR.Records and reports have proved that herb medicine has the biological active constitutent,and flavonoids,tetrandrine,peimine,panaxoside,arsenic disulfide,elemene and other compound herb recipe also has the potency to reverse the MDR effect in vitro,which indicates all the better that herb medicine has a potential clinical application and value of exploitation,and thus deserving our deeper research.
Prunella vulgaris here refers to the dry ripe ear of brunellae cum fructu, belonging to labiatae and Prunella,which has the effectiveness of eyesight improving and endogenous fire clearing,detumescence and stagnation eliminating,this will help to restrain the proliferation of many kinds of tumor cells and to induce apoptosis, however,it is rarely reported about the researching on its reversal effect of multidrug resistance.Zhou Xinying,an graduate student from China medical university,had done some some research and proved that PV can partly reverse the drug fast of breast cancer tumor cells,but similar report has not yet been seen on the research about reversal effect on Raji cells,MDA-MB-435s cells and SMMC-7721 cells.
This research is aimed to use the RT-PCR technology and observe the effect on genetic expression of multidrug resistance in Raji cells,MDA-MB-435s cells and SMMC-7721 cells under different concentrations of PV,and in this way,to approach the mechanism of MDR with the expectation to find the potential drug fast reversal medicine with clinical application prospect.
METHODS
1 The half inhibitory rate(IC_(50)) of Raji cells、MDA-MB-435s cells and SMMC-7721 cells treated with ADM,and ADM in combination with PV were examined by MTT assay,respectively.
2 The effects of different concentrations of Prunella vulgaris on expression of mdr1 gene of Raji cells、MDA-MB-435scells and SMMC-7721 cells were detected with reverse transcriptase polymerase chain reaction(RT-PCR).
RESULTS
1 PV cytotoxicity detection,the depressant effects on Raji cells,MDA-MB-435s cells and SMMC-7721 cells bear a dose-concentration dependence.Through the dose effect curve,non-cytotoxicity dose(growth rate＞95%) could be determined as 10.0μg/ml,20μg/ml and 30μg/ml.The IC_(50) of three tumor cells dealed with PV were 31.67±0.89μg/ml、63.03±1.22μg/ml、81.45±2.16μg/ml respectively.The IC_(50) of three tumor cells dealed with ADM were 1.28±0.66μg/ml、1.87±0.85μg/ml、2.39±1.58μg/ml.We choose the PV of non-cytotoxicity dose combinedwith ADM at its correspondingly different levels of concentrations.The experimental results show that values of IC50 have significant difference(P＜0.05) between the conditions when ADM was solely used against the tumor cells and used with the combination of Prunella vulgaris.
2 The effects of Prunella vulgaris on expression mdr1 gene of tumor cells,from the rusult of study,we can see Raji cells,MDA-MB-435s cells and SMMC-7721 cells exprssion mdr1 gene,the mdr1 gene expression of SMMC-7721 cells were strongest, the mdr1 gene expression of were weakest,which were in line with the degree of resistance of three tumor cells in the clinical.Different concentrations of PV could weaken the expression level of mdr1 gene of Raji cells、MDA-MB-435s cells and SMMC-7721 cells,and with the concentration increasing,the down regulation of expression were more obvious(P＜0.05).
CONCLUSION
1 PV can inhibit Raji cells,MDA-MB-435s cells and SMMC-7721 cells proliferation,and the inhibition were dose-dependent.
2 PV is able to partly reverse the ADM-resistance in Raji cells,MDA-MB-435s cells and SMMC-7721 cells.
3 Three tumor cells have been existed primary multidrug resistance,mdr1 gene over-expression of tumor cells may be the formation of the molecular basis of MDR
4 Different concentrations of PV which under the non-cytotoxic dose could reverse or partly reverse the multidrug resistance by way of weaken the expression level of mdr1 gene.
引文
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