PH II-7作用模式和机理研究
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摘要
第一章PHⅡ-7作用模式和机理研究
多药耐药(multidrug resistance,MDR)是指肿瘤细胞对一种化疗药物出现耐药的同时,对其他结构不同、作用靶位不同的化疗药物亦产生抗药性,是肿瘤化疗失败和复发的根源。多药耐药的产生是多机制作用多基因参与的复杂过程,ATP结合盒(ATP Binding Cassette,ABC)家族基因过表达已被证明是MDR产生的重要原因,MDR1是ABC家族中最早被发现,影响最广泛,最为重要的MDR相关基因,围绕MDR1的MDR机理研究及逆转MDR研究的重要性日益凸显。
多药耐药作为肿瘤化疗中的常见现象,当今仍然是化疗失败和肿瘤病人死亡的最主要原因之一。针对肿瘤MDR的产生过程,应用多药耐药逆转剂是解决肿瘤MDR的主要手段。经过二十多年的开发研究,已发现大量具有MDR逆转活性的化合物,主要包括:钙通道阻滞剂(维拉帕米及其衍生物)、钙调蛋白抑制剂(噻吩嗪类化合物)、免疫抑制剂(环孢菌素A及其衍生物)、类固醇和激素类似物(黄体酮、甲地孕酮)等。但这类逆转剂的毒副作用也使其临床应用受到限制。
中药当归龙荟丸可有效治疗有效治疗慢性粒细胞性白血病,我室以其有效成分靛玉红为模板,经定量构效关系研究,从合成的几十种衍生物中筛选出PHⅡ-7。本实验是对其活性和作用机理进行研究。首先,在杀伤活性试验中,我们通过MTT实验发现PHⅡ-7对K562细胞及其耐药株K562/A02均有明显的杀伤作用,且IC50相近。而K562/A02对作为阳性对照的阿霉素的IC50值则比K562高出近百倍应用表达谱芯片AFFYMETRIX Genome u133 plus2.0辅以SYBR GREEN REALTIME PCR验证,研究PHⅡ-7作用前后的前述两细胞系发现,经典多药耐药基因MDR1表达量下调,与其磷酸化和功能密切相关的基因PKCA显著下调。与S期细胞周期阻滞、凋亡、细胞衰老密切相关的P21,CHK1等基因显著上调。激光共聚焦成像发现PHⅡ-7作用后K562/A02细胞内ADM蓄积明显增加,流式细胞术发现这种降低呈时间依赖性。凋亡和周期实验证明PHⅡ-7作用后细胞周期发生阻滞,细胞凋亡增加。PHⅡ-7可以抑制经典耐药基因MDR1的表达,并可显著抑制PKCA的表达,通过使用SiRNA沉默PKCA的表达发现,K562/A02细胞中PKCA的下调可导致c-FOS,c-JUN和MDR1基因的显著下调,提示PHⅡ-7通过PKCA-AP1-MDR1信号通路下调MDR1基因的表达,从而逆转耐药肿瘤细胞的耐药状态。并通过作用于有关基因导致细胞周期阻滞,并诱导凋亡。PHⅡ-7同时具备了内在肿瘤细胞杀伤活性和通过PKCA通路影响MDRL基因的表达从而具备逆转耐药表型的活性,有可能成为克服肿瘤化疗中多药耐药现象的一种新的解决方案。
第二章SiRNA沉默SORCIN基因表达对K562/A02基因表达谱的影响的研究
目的:以人多药耐药白血病细胞系K562/A02为模型,研究其中高表达的耐药相关基因sorcin的功能及其介导多药耐药的可能机制和涉及的调控通路,为后续研究提供线索,为逆转肿瘤多药耐药提供新的靶点。
方法:设计并用体外转录法合成针对人sorcin基因的小干扰RNA,脂质体法转入K562/A02细胞,提取总RNA并行反转录,应用实时荧光定量PCR(Realtime PCR)法检测sorcin基因表达的抑制效果。通过Affymetrix U133 plus2.0基因表达谱芯片检测干扰组与对照组K562A02细胞转录水平基因表达的差异。结果:成功设计并合成了针对人sorcin基因的siRNA,转染后检测得知sorcin基因的转录抑制率为80%以上,用基因表达谱芯片检测,发现与对照组比较,干扰sorcin导致42个基因显著下调,37个基因显著上调。下调的基因主要包括:FOS,PDGFC,MYO3B;上调的基因主要包括IL8,FGF18,CCNG2。结论:通过特异下调sorcin的表达,筛选干扰组和对照组转录水平差异明显的基因,发现sorcin可能通过调控MDR1表达等主要途径介导K562/A02细胞的多药耐药。其中IL-8、PDGF等表达发生明显变化,提示sorcin介导K562/A02细胞耐药可能与c-FOS,IL-8和PDGF等有关。
Although concepts and technologies have evolved greatly on cancer therapy,but most clinical cancer treatments still rely on chemotherapy,especially for metastasis cancer and haematological malignancies.The major obstacle to chemotherapy is that tumor cells treated with chemotherapy agents commonly develop resistance to a variety of structurally and mechanistically unrelated drugs,the phenomenon is called multidrug resistance(MDR).In previous study,from traditional Chinese medicine Danggui Longhui Wan,to indigo naturalis,from indigo naturalis to indirubin,in previous study, the activity of Danggui Longhui Wan was traced more and more precisely.Our lab identified the active subunit of,and synthesized a series of derivatives based on the active subunit and screened out the PHⅡ-7.
The MDR cell lines was highly resistant to ADM,the resistance fold of K562/A02, MCF7/ADR and HL60/ADR compared with their parental cell lines are 93.93,25.16,182.3 folds respectively,which explains the trouble caused by MDR phenomenon in clinical chemotherapy.As to PHⅡ-7 the IC50 values had no significant difference or much lower difference than ADM between the cell lines and their corresponding MDR sublines, suggesting that PHⅡ-7 is highly effective against MDR phenotype cells compared with ADM.
we applied genomic and chemical approaches in researches related with ancient traditional Chinese medicine.To unravel the action mode of PHⅡ-7,we analyzed the genome profiling changes in PHⅡ-7 treated K562 and K562/A02 cells.The result guided our study to two aspects affected by PHⅡ-7:its regulation of MDR1 gene expression, and its influence on apoptosis and cell cycle.
A dramatic decrease in ADM attainment in K562/A02 cells than in K562 cells was illustrated by CSLM imaging,comparatively,the intracellular intention of FITC labeled PHⅡ-7 did not significantly vary between the K562 and K562/A02 cells,the PHⅡ-7 molecules just redistributed into nucleus time dependently,rather than being pumped out of the cells like ADM,providing direct evidence that PHⅡ-7 is not influenced by drug efflux mediated MDR mechanism.Very low concentration(＜IC10)PHⅡ-7 pre-treated K562/A02 cells showed attenuated drug efflux,time and dose dependently.Genome profiling indicated that the MDR1 expression level significantly decreased after the treatment,which confirmed that PHⅡ-7 inhibited MDR1 expression.Meanwhile,the expression level of protein kinase C alpha(PKCA) substantially decreased.We further analyzed the relationship between the expression of the two genes by knockout of PKCA expression by RNAi,which resulted in significant reduction in MDR1 expression, indicating that PHⅡ-7 impeded MDR1 expression by inhibition of PKCA transcription.We also found substantially decreased expression of c-FOS and c-JUN,in PHⅡ-7 treated group and RNAi group.PHⅡ-7 treated K562/A02 cells significantly decreased the expression of PKCA,c-FOS,c-JUN,and MDR1,which is detected by Genome profiling, RNAi knockout of PKCA expression in K562/A02 cells also resulted in salient reduction in expression of c-FOS,c-JUN and MDR1,which is consistent with the result of PHⅡ-7 treatment,indicating a positive correlation between PKCA,AP1 and MDR1 expression.
According to our data,100nM ADM induced significant apoptosis in K562 cells,but failed to do so in K562/A02 cells.Notably K562 and K562/A02 cells treated with PHⅡ-7 were induced apoptosis without considerable difference at three concentrations, indicate that PHⅡ-7 is capable of overcome apoptosis resistance and induce significant apoptosis in K562/A02 cells.Genome profiling and gene expression analysis shed light on the possible underlying mechanism of PHⅡ-7 induced apoptosis,The apoptosis related gene PML(promyelocytic leukemia) were significantly up-regulated,PML is essential for multiple apoptotic pathways.Analysis of mice and cells lacking PML has demonstrated that PML is involved in various apoptotic pathways.
Previous studies have demonstrated that certain indirubin derivatives are capable of inducing cell cycle arrest in cancer cells.Our data indicate that PHⅡ-7 substantially inhibit cell cycle of both K562 and K562/A02 cells in S phase.Cells inhibited in S phase are not able to enter G2 and M phase,thus were prohibited from mitosis and further proliferation.The temporal order of many critical cell cycle events must be strictly maintained to ensure cell survival and integrity.A simple example is that of genome duplication which must be completed before cell division.Our genome profiling data revealed several PHⅡ-7 responsive genes are related with cell cycle control,such as HBP1,CHK1 and P21.The findings were confirmed by RT-qPCR gene expression analysis,expression level of CHK1 increased after PHⅡ-7 treatment in both K562 and K562/A02 cells.CHK1 is apparently necessary for an intra-S phase checkpoint,ensuring that activation of late replication origins is blocked and arrested replication fork integrity is maintained when DNA synthesis is inhibited.Increased P21 expression also contributes to S phase arrest.High p21 producing cells move much more slowly through S phase,p21 protein can elevate E2F-1 activity to arrest a substantial subset of cells in S phase.
Judging by our data,PHⅡ-7 substantially induced apoptosis and S phase cell cycle arrest in MDR tumor cells,by regulation of specific gene expression,and finally resulted in effective inhibition and termination of MDR tumor growth,it is a promising lead compound for anti-MDR tumor drug development,and may represents a new solution for MDR phenomenon which is still the major cause for tumor therapy failure and patient death.Our way of discovering PHⅡ-7,represents an effective mode of lead compound discovery based on traditional Chinese medicine.
Objective:to investigate the function of sorcin in multidrug resistance in MDR human leukemia cell line K562/A02 and to uncover the mechanisms and signal transduction pathways related.Methods:sorcin-targeting small interfering RNA was successfully designed and synthesized to inhibit the expression of sorcin in K562/A02 cells.The inhibition of sorcin was validated by realtime RT PCR.Then,the global gene expression profile was tested by Affymetrix U133 plus 2.0 microarray and the differences in gene expression was obtained comparing to K562/A02 cells untreated.
Results:knock-down of sorcin induced variation in the expression level of a series of genes.Including c-FOS,PDGF-C and IL-8.Conclusion:Sorcin may influence the multidrug resistance phenotype by altering the transcription level of c-FOS,PDGF-C and IL-8.
多药耐药(multidrug resistance,MDR)是指肿瘤细胞对一种化疗药物出现耐药的同时,对其他结构不同、作用靶位不同的化疗药物亦产生抗药性,是肿瘤化疗失败和复发的根源。多药耐药的产生是多机制作用多基因参与的复杂过程,ATP结合盒(ATP Binding Cassette,ABC)家族基因过表达已被证明是MDR产生的重要原因,MDR1是ABC家族中最早被发现,影响最广泛,最为重要的MDR相关基因,围绕MDR1的MDR机理研究及逆转MDR研究的重要性日益凸显。
多药耐药作为肿瘤化疗中的常见现象,当今仍然是化疗失败和肿瘤病人死亡的最主要原因之一。针对肿瘤MDR的产生过程,应用多药耐药逆转剂是解决肿瘤MDR的主要手段。经过二十多年的开发研究,已发现大量具有MDR逆转活性的化合物,主要包括:钙通道阻滞剂(维拉帕米及其衍生物)、钙调蛋白抑制剂(噻吩嗪类化合物)、免疫抑制剂(环孢菌素A及其衍生物)、类固醇和激素类似物(黄体酮、甲地孕酮)等。但这类逆转剂的毒副作用也使其临床应用受到限制。
中药当归龙荟丸可有效治疗有效治疗慢性粒细胞性白血病,我室以其有效成分靛玉红为模板,经定量构效关系研究,从合成的几十种衍生物中筛选出PHⅡ-7。本实验是对其活性和作用机理进行研究。首先,在杀伤活性试验中,我们通过MTT实验发现PHⅡ-7对K562细胞及其耐药株K562/A02均有明显的杀伤作用,且IC50相近。而K562/A02对作为阳性对照的阿霉素的IC50值则比K562高出近百倍应用表达谱芯片AFFYMETRIX Genome u133 plus2.0辅以SYBR GREEN REALTIME PCR验证,研究PHⅡ-7作用前后的前述两细胞系发现,经典多药耐药基因MDR1表达量下调,与其磷酸化和功能密切相关的基因PKCA显著下调。与S期细胞周期阻滞、凋亡、细胞衰老密切相关的P21,CHK1等基因显著上调。激光共聚焦成像发现PHⅡ-7作用后K562/A02细胞内ADM蓄积明显增加,流式细胞术发现这种降低呈时间依赖性。凋亡和周期实验证明PHⅡ-7作用后细胞周期发生阻滞,细胞凋亡增加。PHⅡ-7可以抑制经典耐药基因MDR1的表达,并可显著抑制PKCA的表达,通过使用SiRNA沉默PKCA的表达发现,K562/A02细胞中PKCA的下调可导致c-FOS,c-JUN和MDR1基因的显著下调,提示PHⅡ-7通过PKCA-AP1-MDR1信号通路下调MDR1基因的表达,从而逆转耐药肿瘤细胞的耐药状态。并通过作用于有关基因导致细胞周期阻滞,并诱导凋亡。PHⅡ-7同时具备了内在肿瘤细胞杀伤活性和通过PKCA通路影响MDRL基因的表达从而具备逆转耐药表型的活性,有可能成为克服肿瘤化疗中多药耐药现象的一种新的解决方案。
第二章SiRNA沉默SORCIN基因表达对K562/A02基因表达谱的影响的研究
目的:以人多药耐药白血病细胞系K562/A02为模型,研究其中高表达的耐药相关基因sorcin的功能及其介导多药耐药的可能机制和涉及的调控通路,为后续研究提供线索,为逆转肿瘤多药耐药提供新的靶点。
方法:设计并用体外转录法合成针对人sorcin基因的小干扰RNA,脂质体法转入K562/A02细胞,提取总RNA并行反转录,应用实时荧光定量PCR(Realtime PCR)法检测sorcin基因表达的抑制效果。通过Affymetrix U133 plus2.0基因表达谱芯片检测干扰组与对照组K562A02细胞转录水平基因表达的差异。结果:成功设计并合成了针对人sorcin基因的siRNA,转染后检测得知sorcin基因的转录抑制率为80%以上,用基因表达谱芯片检测,发现与对照组比较,干扰sorcin导致42个基因显著下调,37个基因显著上调。下调的基因主要包括:FOS,PDGFC,MYO3B;上调的基因主要包括IL8,FGF18,CCNG2。结论:通过特异下调sorcin的表达,筛选干扰组和对照组转录水平差异明显的基因,发现sorcin可能通过调控MDR1表达等主要途径介导K562/A02细胞的多药耐药。其中IL-8、PDGF等表达发生明显变化,提示sorcin介导K562/A02细胞耐药可能与c-FOS,IL-8和PDGF等有关。
Although concepts and technologies have evolved greatly on cancer therapy,but most clinical cancer treatments still rely on chemotherapy,especially for metastasis cancer and haematological malignancies.The major obstacle to chemotherapy is that tumor cells treated with chemotherapy agents commonly develop resistance to a variety of structurally and mechanistically unrelated drugs,the phenomenon is called multidrug resistance(MDR).In previous study,from traditional Chinese medicine Danggui Longhui Wan,to indigo naturalis,from indigo naturalis to indirubin,in previous study, the activity of Danggui Longhui Wan was traced more and more precisely.Our lab identified the active subunit of,and synthesized a series of derivatives based on the active subunit and screened out the PHⅡ-7.
The MDR cell lines was highly resistant to ADM,the resistance fold of K562/A02, MCF7/ADR and HL60/ADR compared with their parental cell lines are 93.93,25.16,182.3 folds respectively,which explains the trouble caused by MDR phenomenon in clinical chemotherapy.As to PHⅡ-7 the IC50 values had no significant difference or much lower difference than ADM between the cell lines and their corresponding MDR sublines, suggesting that PHⅡ-7 is highly effective against MDR phenotype cells compared with ADM.
we applied genomic and chemical approaches in researches related with ancient traditional Chinese medicine.To unravel the action mode of PHⅡ-7,we analyzed the genome profiling changes in PHⅡ-7 treated K562 and K562/A02 cells.The result guided our study to two aspects affected by PHⅡ-7:its regulation of MDR1 gene expression, and its influence on apoptosis and cell cycle.
A dramatic decrease in ADM attainment in K562/A02 cells than in K562 cells was illustrated by CSLM imaging,comparatively,the intracellular intention of FITC labeled PHⅡ-7 did not significantly vary between the K562 and K562/A02 cells,the PHⅡ-7 molecules just redistributed into nucleus time dependently,rather than being pumped out of the cells like ADM,providing direct evidence that PHⅡ-7 is not influenced by drug efflux mediated MDR mechanism.Very low concentration(＜IC10)PHⅡ-7 pre-treated K562/A02 cells showed attenuated drug efflux,time and dose dependently.Genome profiling indicated that the MDR1 expression level significantly decreased after the treatment,which confirmed that PHⅡ-7 inhibited MDR1 expression.Meanwhile,the expression level of protein kinase C alpha(PKCA) substantially decreased.We further analyzed the relationship between the expression of the two genes by knockout of PKCA expression by RNAi,which resulted in significant reduction in MDR1 expression, indicating that PHⅡ-7 impeded MDR1 expression by inhibition of PKCA transcription.We also found substantially decreased expression of c-FOS and c-JUN,in PHⅡ-7 treated group and RNAi group.PHⅡ-7 treated K562/A02 cells significantly decreased the expression of PKCA,c-FOS,c-JUN,and MDR1,which is detected by Genome profiling, RNAi knockout of PKCA expression in K562/A02 cells also resulted in salient reduction in expression of c-FOS,c-JUN and MDR1,which is consistent with the result of PHⅡ-7 treatment,indicating a positive correlation between PKCA,AP1 and MDR1 expression.
According to our data,100nM ADM induced significant apoptosis in K562 cells,but failed to do so in K562/A02 cells.Notably K562 and K562/A02 cells treated with PHⅡ-7 were induced apoptosis without considerable difference at three concentrations, indicate that PHⅡ-7 is capable of overcome apoptosis resistance and induce significant apoptosis in K562/A02 cells.Genome profiling and gene expression analysis shed light on the possible underlying mechanism of PHⅡ-7 induced apoptosis,The apoptosis related gene PML(promyelocytic leukemia) were significantly up-regulated,PML is essential for multiple apoptotic pathways.Analysis of mice and cells lacking PML has demonstrated that PML is involved in various apoptotic pathways.
Previous studies have demonstrated that certain indirubin derivatives are capable of inducing cell cycle arrest in cancer cells.Our data indicate that PHⅡ-7 substantially inhibit cell cycle of both K562 and K562/A02 cells in S phase.Cells inhibited in S phase are not able to enter G2 and M phase,thus were prohibited from mitosis and further proliferation.The temporal order of many critical cell cycle events must be strictly maintained to ensure cell survival and integrity.A simple example is that of genome duplication which must be completed before cell division.Our genome profiling data revealed several PHⅡ-7 responsive genes are related with cell cycle control,such as HBP1,CHK1 and P21.The findings were confirmed by RT-qPCR gene expression analysis,expression level of CHK1 increased after PHⅡ-7 treatment in both K562 and K562/A02 cells.CHK1 is apparently necessary for an intra-S phase checkpoint,ensuring that activation of late replication origins is blocked and arrested replication fork integrity is maintained when DNA synthesis is inhibited.Increased P21 expression also contributes to S phase arrest.High p21 producing cells move much more slowly through S phase,p21 protein can elevate E2F-1 activity to arrest a substantial subset of cells in S phase.
Judging by our data,PHⅡ-7 substantially induced apoptosis and S phase cell cycle arrest in MDR tumor cells,by regulation of specific gene expression,and finally resulted in effective inhibition and termination of MDR tumor growth,it is a promising lead compound for anti-MDR tumor drug development,and may represents a new solution for MDR phenomenon which is still the major cause for tumor therapy failure and patient death.Our way of discovering PHⅡ-7,represents an effective mode of lead compound discovery based on traditional Chinese medicine.
Objective:to investigate the function of sorcin in multidrug resistance in MDR human leukemia cell line K562/A02 and to uncover the mechanisms and signal transduction pathways related.Methods:sorcin-targeting small interfering RNA was successfully designed and synthesized to inhibit the expression of sorcin in K562/A02 cells.The inhibition of sorcin was validated by realtime RT PCR.Then,the global gene expression profile was tested by Affymetrix U133 plus 2.0 microarray and the differences in gene expression was obtained comparing to K562/A02 cells untreated.
Results:knock-down of sorcin induced variation in the expression level of a series of genes.Including c-FOS,PDGF-C and IL-8.Conclusion:Sorcin may influence the multidrug resistance phenotype by altering the transcription level of c-FOS,PDGF-C and IL-8.
引文
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