新型Hsp90抑制剂-SNX-2112治疗人慢性髓细胞白血病机制研究
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摘要
SNX-2112是近几年筛选出的一种新型Hsp90抑制剂,它可以特异性与Hsp90家族ATPpocket结合,抑制Hsp90活性,诱导Hsp90受体蛋白降解,最终导致肿瘤细胞的凋亡,是一种具有开发前景的抗肿瘤药物,但SNX-2112作用的具体分子机制不详。
本研究以人慢性髓细胞白血病细胞系K562为细胞模型,采用MTT法、Annexin-v/PI荧光染色法、流式细胞技术和Western Blot等方法,检测SNX-2112对K562细胞增殖、凋亡及caspase家族蛋白质表达的影响,结果表明SNX-2112(0.05-10μM)可以抑制K562细胞的增殖(IC_(50)=0.92μM)并诱导其凋亡(凋亡率为10.6±2.1-75.8±7.4%)。在0.1-10μM范围内SNX-2112可以引起caspase-3,9和PARP前体活化,具有剂量依赖性。
利用全基因组表达谱芯片对1μM SNX-2112作用48 h后K562细胞的全基因组cDNA表达进行了检测,G0分析发现229个基因(占检出基因的10.75%)与线粒体功能有关,尤以线粒体代谢相关基因显著(占62.51%),这一结果也为SNX-2112引起线粒体功能损伤提供了依据。
通过双向凝胶电泳,获得药物作用细胞的双向电泳图谱,MALDI TOF/TOF质谱仪对差异表达的蛋白质点进行鉴定证实了55个差异点,生物信息学方法将这些蛋白质按功能进行分类发现有7个差异点与线粒体功能相关。
最后进一步研究了SNX-2112诱导K562细胞凋亡的机制。结合检出的Caspase家族活化通路和转录组与蛋白质组学的研究结果我们推断SNX-2112通过线粒体损伤的内源性通路介导了K562细胞凋亡。JC-1染色实验和cyto-c释放的Western Blot检测证实了这一结论。蛋白质组学的研究中鉴定出的差异蛋白质CRKL和Grb2为我们揭示出线粒体功能损伤的上游信号部分来自于Akt信号转导通路,Western Blot和co-IP实验证明了这一点。
体内实验选用尾静脉接种K562细胞的NOD/SCID小鼠作为慢性髓细胞白血病模型。接种小鼠给予SNX-2112(6mg/kg,iv)处理,同时分别设立17-AAG和阴性对照组。观察各组小鼠存活时间、测定人慢性白血病表面抗原CD13,CD33。结果表明SNX-2112可以抑制小鼠体内白血病细胞增殖,延长其生存期。
本研究证明SNX-2112具有潜在的体外、体内慢性白血病治疗活性,并探索了该化合物抗肿瘤的部分作用机制,为进一步开发具有自主知识产Hsp90抑制剂药物建立了理论基础。
SNX-2112 is a novel screened Hsp90 inhibitor in recent years,which can specifically bind ATP pocket of Hsp90 families,inhibit the latter activity and induce their client proteins degradation resulting in cancer cell apoptosis,therefore currently SNX-2112 is considered to be a promising anti-cancer drug for exploring.However the molecular mechanism of the apoptosis effect of SNX-2112 is poorly understood.
In vitro experiments using human chronic myeloid leukemia K562 cell line as a study model,we detected SNX-2112 effect on the proliferation,apoptosis and caspase families expression of K562 cells by employing MTT methods,Annexin-v/PI fluorescent staining,flow cytomertry,Westem blot analysis and etc,.Our results showed that 0.05-10μM SNX-2112 could reduce cells growth ration with IC_(50)=0.92μM and lead to apoptosis(the percentages covering from 10.6±2.1 to 75.8±7.4). Additionally,at 0.1-10μM concentrations,SNX-2112 activated pro-caspase-3,9 and PARP in a dose-dependent manner.
Utilizing genomics expression profile chips we detected the total cDNA expression levels of K562 cells treated 1μM SNX-2112 for 48 h.By Gene Ontology analysis,we found 229 different genes related with mitochondrial function,particularly in metabolism groups with a notable significance(accounting for 62.15%of total selectors),which also provided evidence for mitochondrial dysfunction due to SNX-2112 action.
2-D gel electrophoresis was performed to obtain K562 cells proteomics profiles induced by SNX-2112. MALDI TOF/TOF mass spectrometer identified 55 different protein dots,7 of which involve in mitochondrial impairment analyzed by function classification with bioinformatics.
Next,we studied the possible mechanism of K562 apoptosis produced by SNX-2112.Together with the detected caspase activated pathway,transcriptomic and proteomic data,we speculated that SNX-2112 regulated K562 cells apoptosis mediated by the intrinsic pathway of mitochondrial impairment,which is further supported by JC-1 staining assay and Western Blot of cyto-c release. The two proteins,CRKL and Grb2,identified by proteomics study disclosed the up-stream signalinging partly originated from Akt signaling transduction pathway,tested by Western Blot and co-IP approaches.
We tested the effect of SNX-2112 on NOD/SCID mice model inoculated with K562 cells.The implanted mice were treated with SNX-2112(6mg/kg,ⅳ).Simultaneously we also set 17-AAG and negative control groups,respectively.Mice survival time and expression of human chronic leukemia antigens(CD13 and CD33) were served as therapy criteria.SNX-2112 inhibited leukemia cells proliferation in vivo and prolonged the survival time of NOD/SCID mice inoculated with K562 tumor cells.
In conclusion,our results demonstrated the therapeutic potential of SNX-2112 against human chronic myeloid leukemia and found its partial anti-cancer mechanism,all of which establish theory base for further researching Hsp90 inhibitors with self-owned intellectual property rights.
本研究以人慢性髓细胞白血病细胞系K562为细胞模型,采用MTT法、Annexin-v/PI荧光染色法、流式细胞技术和Western Blot等方法,检测SNX-2112对K562细胞增殖、凋亡及caspase家族蛋白质表达的影响,结果表明SNX-2112(0.05-10μM)可以抑制K562细胞的增殖(IC_(50)=0.92μM)并诱导其凋亡(凋亡率为10.6±2.1-75.8±7.4%)。在0.1-10μM范围内SNX-2112可以引起caspase-3,9和PARP前体活化,具有剂量依赖性。
利用全基因组表达谱芯片对1μM SNX-2112作用48 h后K562细胞的全基因组cDNA表达进行了检测,G0分析发现229个基因(占检出基因的10.75%)与线粒体功能有关,尤以线粒体代谢相关基因显著(占62.51%),这一结果也为SNX-2112引起线粒体功能损伤提供了依据。
通过双向凝胶电泳,获得药物作用细胞的双向电泳图谱,MALDI TOF/TOF质谱仪对差异表达的蛋白质点进行鉴定证实了55个差异点,生物信息学方法将这些蛋白质按功能进行分类发现有7个差异点与线粒体功能相关。
最后进一步研究了SNX-2112诱导K562细胞凋亡的机制。结合检出的Caspase家族活化通路和转录组与蛋白质组学的研究结果我们推断SNX-2112通过线粒体损伤的内源性通路介导了K562细胞凋亡。JC-1染色实验和cyto-c释放的Western Blot检测证实了这一结论。蛋白质组学的研究中鉴定出的差异蛋白质CRKL和Grb2为我们揭示出线粒体功能损伤的上游信号部分来自于Akt信号转导通路,Western Blot和co-IP实验证明了这一点。
体内实验选用尾静脉接种K562细胞的NOD/SCID小鼠作为慢性髓细胞白血病模型。接种小鼠给予SNX-2112(6mg/kg,iv)处理,同时分别设立17-AAG和阴性对照组。观察各组小鼠存活时间、测定人慢性白血病表面抗原CD13,CD33。结果表明SNX-2112可以抑制小鼠体内白血病细胞增殖,延长其生存期。
本研究证明SNX-2112具有潜在的体外、体内慢性白血病治疗活性,并探索了该化合物抗肿瘤的部分作用机制,为进一步开发具有自主知识产Hsp90抑制剂药物建立了理论基础。
SNX-2112 is a novel screened Hsp90 inhibitor in recent years,which can specifically bind ATP pocket of Hsp90 families,inhibit the latter activity and induce their client proteins degradation resulting in cancer cell apoptosis,therefore currently SNX-2112 is considered to be a promising anti-cancer drug for exploring.However the molecular mechanism of the apoptosis effect of SNX-2112 is poorly understood.
In vitro experiments using human chronic myeloid leukemia K562 cell line as a study model,we detected SNX-2112 effect on the proliferation,apoptosis and caspase families expression of K562 cells by employing MTT methods,Annexin-v/PI fluorescent staining,flow cytomertry,Westem blot analysis and etc,.Our results showed that 0.05-10μM SNX-2112 could reduce cells growth ration with IC_(50)=0.92μM and lead to apoptosis(the percentages covering from 10.6±2.1 to 75.8±7.4). Additionally,at 0.1-10μM concentrations,SNX-2112 activated pro-caspase-3,9 and PARP in a dose-dependent manner.
Utilizing genomics expression profile chips we detected the total cDNA expression levels of K562 cells treated 1μM SNX-2112 for 48 h.By Gene Ontology analysis,we found 229 different genes related with mitochondrial function,particularly in metabolism groups with a notable significance(accounting for 62.15%of total selectors),which also provided evidence for mitochondrial dysfunction due to SNX-2112 action.
2-D gel electrophoresis was performed to obtain K562 cells proteomics profiles induced by SNX-2112. MALDI TOF/TOF mass spectrometer identified 55 different protein dots,7 of which involve in mitochondrial impairment analyzed by function classification with bioinformatics.
Next,we studied the possible mechanism of K562 apoptosis produced by SNX-2112.Together with the detected caspase activated pathway,transcriptomic and proteomic data,we speculated that SNX-2112 regulated K562 cells apoptosis mediated by the intrinsic pathway of mitochondrial impairment,which is further supported by JC-1 staining assay and Western Blot of cyto-c release. The two proteins,CRKL and Grb2,identified by proteomics study disclosed the up-stream signalinging partly originated from Akt signaling transduction pathway,tested by Western Blot and co-IP approaches.
We tested the effect of SNX-2112 on NOD/SCID mice model inoculated with K562 cells.The implanted mice were treated with SNX-2112(6mg/kg,ⅳ).Simultaneously we also set 17-AAG and negative control groups,respectively.Mice survival time and expression of human chronic leukemia antigens(CD13 and CD33) were served as therapy criteria.SNX-2112 inhibited leukemia cells proliferation in vivo and prolonged the survival time of NOD/SCID mice inoculated with K562 tumor cells.
In conclusion,our results demonstrated the therapeutic potential of SNX-2112 against human chronic myeloid leukemia and found its partial anti-cancer mechanism,all of which establish theory base for further researching Hsp90 inhibitors with self-owned intellectual property rights.
引文
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