7-木糖-10-去乙酰基紫杉醇抗肿瘤活性与作用机制
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摘要
东北红豆杉(Taxus.cuspidata)的水提液在我国被用于治疗癌症,表明东北红豆杉(Taxus.cuspidata)的水提液中含有抗癌的活性物质。在寻找东北红豆杉(Taxus.cuspidata)中的抗癌的活性物质过程中,一种亲水性紫杉醇衍生物7-木糖-10-去乙酰基紫杉醇被筛选出来。并首次对7-木糖-10-去乙酰基紫杉醇的抗肿瘤活性和机制进行了系统的研究,研究结果如下:
1.对小鼠肿瘤S-180以10mg/kg的剂量7-木糖-10-去乙酰基紫杉醇静脉给药,小鼠肿瘤S-180的抑制率为68.2%,阳性对照紫杉醇抑制率为59.4%。首次证明7-木糖-10-去乙酰基紫杉醇有较好的抗肿瘤活性。
2.首次建立了HPLC-MS/MS测定大鼠血浆中7-木糖-10-去乙酰基紫杉醇的含量的方法,结果表明在较低剂量2.5mg/kg静脉给药7-木糖-10-去乙酰基紫杉醇时,7-木糖-10-去乙酰基紫杉醇在大鼠体内有较高的血药浓度,最高峰为500ng/mL左右。
3.通过MTT的方法研究了7-木糖-10-去乙酰基紫杉醇对MCF-7乳腺癌肿瘤细胞、A549肺癌细胞、CEM淋巴癌肿瘤细胞、PC-3前列腺癌肿瘤细胞的抗肿瘤活性,结果表明PC-3前列腺癌肿瘤细胞对7-木糖-10-去乙酰基紫杉醇较敏感,IC_(50)在48h为5μM,在72h为586nM。
4.通过流式细胞仪、DNA laddering、激光共聚焦显微镜、透射电镜等方法研究了7-木糖-10-去乙酰基紫杉醇诱导PC-3前列腺癌肿瘤细胞细胞毒的机制,阐明了7-木糖-10-去乙酰基紫杉醇产生细胞毒的机制为诱导PC-3前列腺癌细胞产生凋亡。
5.通过流式细胞仪、Westen blotting实验和原子力显微镜,首次阐明了7-木糖-10-去乙酰基紫杉醇诱导PC-3前列腺癌肿瘤细胞发生凋亡的细胞信号通路,此通路与紫杉醇诱导肿瘤细胞发生细胞凋亡的通路不完全相同。具体通路如下:
7-木糖-10-去乙酰基紫杉醇引起了PC-3前列腺癌肿瘤细胞显著的有丝分裂阻滞,接着伴随着促凋亡和抗凋亡的Bcl-2家族成员蛋白表达的明显改变。上调Bad蛋白表达和下调Bcl-X_L蛋白表达是其中关键过程,这个过程破坏了线粒体膜的通透性并激活了下游的caspase-9,caspase-9又激活下游的caspase-3、-6,也可能有caspase-7,继而发生PC-3前列腺癌肿瘤细胞的凋亡。同时,Bid被caspase-3截断并激活,最终通过下调Bcl-2蛋白的表达和上调Bax蛋白的表达维持并放大线粒体途径的细胞死亡信号。然而,Caspase-8、-10、Fas、TNF-α死亡受体通路似乎没有涉及到7-木糖-10-去乙酰基紫杉醇引起了PC-3前列腺癌肿瘤细胞的凋亡。
本研究论文对7-木糖-10-去乙酰基紫杉醇的抗肿瘤活性和作用机制的系统研究,不仅揭示了亲水性紫杉烷类具有较好的抗肿瘤活性和独特的作用机制,而且还为开发第二代水溶性紫杉醇类新药打下了坚实的科学基础,具有较好应用价值。
Water decoctions from the leaves of Taxus.cuspidata are used in traditional chinese medicine to treat cancer,indicating that water soluble constituents of this tree may indeed possess anticancer activity.In an effort to search for natural products from Taxus.cuspidata with improved pharmacological features compared to paclitaxel,7-xylosyl-10-deacetylpaclitaxel has been isolated and identified by our group.This is a naturally occurring xyloside,which has been shown to possess higher water solubility than paclitaxel.The mode of action of 7-xylosyl-10-deacetylpaclitaxel is scarcely known as of yet.So 7-xylosyl-10-deacetylpaclitaxel was first time systematicly studied on antineoplsamic activity and mechanism,and the results showed that:
1.We first time discovered that inhibitory rate of 7-xylosyl-10-deacetylpaclitaxel was similar to that of paclitaxel through calculating S-180 tumor weight in mice via v.i(Inhibitory rate of 7-xylosyl-10-deacetylpaclitaxel was 68.2%,inhibitory rate of paclitaxel was 59.4%).
2.A simple,rapid and sensitive liquid chromatography-mass spectrometry(LC-MS /MS) method for quantitating 7-xylosyl-10-deacetylpaclitaxel and paclitaxel in rat plasma was established.Approximating 500ng/mL 7-xylosyl-10-deacetylpaclitaxel was first time determinated in rats plasma after v.i.administration of 2.5mg/kg 7-xylosyl- 10-deacetylpaclitaxel.
3.Antitumor activity of 7-xylosyl-10-deacetylpaclitaxel was first time determinated in MCF-7、A549、CEM、PC-3 human cancer cells through MTT method.And PC-3 human prostate cancer cells were sensitive to 7-xylosyl-10-deacetylpaclitaxel(48h IC_(50):5μM,72h IC_(50):586nM).
4.We first time discovered that 7-xylosyl-10-deacetylpaclitaxel induced PC-3 human prostate cancer cells apoptosis as measured by flow cytometry,DNA laddering,laser confocal microscopy、transmission electron microscopy and atomic force microscopy.
5.We first time discovered that pathway of 7-xylosyl-10-deacetylpaclitaxel-triggered apoptosis in PC-3 human prostate cancer cells:
an up-regulation of pro-apoptotic Bax and Bad protein expression and a down-regulation of anti-apoptotic Bcl-2 and Bcl-X_L expression,which lead to a disturbance of the mitochondrial membrane permeability and to the activation of caspase-9.In turn, caspase-9 activated downstream caspases-3 and -6,but not caspase-8.Bid was also activated by caspase-3.Reversely,treatment with a caspase-10-specific inhibitor could not protect PC-3 cells from 7-xylosyl-10-deacetylpaclitaxel-triggered apoptosis. Moreover,7-xylosyl-10-deacetylpaclitaxel had no effect on the expression of CD95 and NF-κB proteins,indicating that apoptosis was induced through the mitochondrial-dependent pathway in PC-3 cells.
The pathway of 7-xylosyl-10-deacetylpaclitaxel-triggered apoptosis was different to the pathway of paclitaxel-triggered apoptosis.
In summary,Systematic study on antitumor activity and mechanism of 7-xylosyl-10 -deacetylpaclitaxel established substantial basis to develop new drug.
1.对小鼠肿瘤S-180以10mg/kg的剂量7-木糖-10-去乙酰基紫杉醇静脉给药,小鼠肿瘤S-180的抑制率为68.2%,阳性对照紫杉醇抑制率为59.4%。首次证明7-木糖-10-去乙酰基紫杉醇有较好的抗肿瘤活性。
2.首次建立了HPLC-MS/MS测定大鼠血浆中7-木糖-10-去乙酰基紫杉醇的含量的方法,结果表明在较低剂量2.5mg/kg静脉给药7-木糖-10-去乙酰基紫杉醇时,7-木糖-10-去乙酰基紫杉醇在大鼠体内有较高的血药浓度,最高峰为500ng/mL左右。
3.通过MTT的方法研究了7-木糖-10-去乙酰基紫杉醇对MCF-7乳腺癌肿瘤细胞、A549肺癌细胞、CEM淋巴癌肿瘤细胞、PC-3前列腺癌肿瘤细胞的抗肿瘤活性,结果表明PC-3前列腺癌肿瘤细胞对7-木糖-10-去乙酰基紫杉醇较敏感,IC_(50)在48h为5μM,在72h为586nM。
4.通过流式细胞仪、DNA laddering、激光共聚焦显微镜、透射电镜等方法研究了7-木糖-10-去乙酰基紫杉醇诱导PC-3前列腺癌肿瘤细胞细胞毒的机制,阐明了7-木糖-10-去乙酰基紫杉醇产生细胞毒的机制为诱导PC-3前列腺癌细胞产生凋亡。
5.通过流式细胞仪、Westen blotting实验和原子力显微镜,首次阐明了7-木糖-10-去乙酰基紫杉醇诱导PC-3前列腺癌肿瘤细胞发生凋亡的细胞信号通路,此通路与紫杉醇诱导肿瘤细胞发生细胞凋亡的通路不完全相同。具体通路如下:
7-木糖-10-去乙酰基紫杉醇引起了PC-3前列腺癌肿瘤细胞显著的有丝分裂阻滞,接着伴随着促凋亡和抗凋亡的Bcl-2家族成员蛋白表达的明显改变。上调Bad蛋白表达和下调Bcl-X_L蛋白表达是其中关键过程,这个过程破坏了线粒体膜的通透性并激活了下游的caspase-9,caspase-9又激活下游的caspase-3、-6,也可能有caspase-7,继而发生PC-3前列腺癌肿瘤细胞的凋亡。同时,Bid被caspase-3截断并激活,最终通过下调Bcl-2蛋白的表达和上调Bax蛋白的表达维持并放大线粒体途径的细胞死亡信号。然而,Caspase-8、-10、Fas、TNF-α死亡受体通路似乎没有涉及到7-木糖-10-去乙酰基紫杉醇引起了PC-3前列腺癌肿瘤细胞的凋亡。
本研究论文对7-木糖-10-去乙酰基紫杉醇的抗肿瘤活性和作用机制的系统研究,不仅揭示了亲水性紫杉烷类具有较好的抗肿瘤活性和独特的作用机制,而且还为开发第二代水溶性紫杉醇类新药打下了坚实的科学基础,具有较好应用价值。
Water decoctions from the leaves of Taxus.cuspidata are used in traditional chinese medicine to treat cancer,indicating that water soluble constituents of this tree may indeed possess anticancer activity.In an effort to search for natural products from Taxus.cuspidata with improved pharmacological features compared to paclitaxel,7-xylosyl-10-deacetylpaclitaxel has been isolated and identified by our group.This is a naturally occurring xyloside,which has been shown to possess higher water solubility than paclitaxel.The mode of action of 7-xylosyl-10-deacetylpaclitaxel is scarcely known as of yet.So 7-xylosyl-10-deacetylpaclitaxel was first time systematicly studied on antineoplsamic activity and mechanism,and the results showed that:
1.We first time discovered that inhibitory rate of 7-xylosyl-10-deacetylpaclitaxel was similar to that of paclitaxel through calculating S-180 tumor weight in mice via v.i(Inhibitory rate of 7-xylosyl-10-deacetylpaclitaxel was 68.2%,inhibitory rate of paclitaxel was 59.4%).
2.A simple,rapid and sensitive liquid chromatography-mass spectrometry(LC-MS /MS) method for quantitating 7-xylosyl-10-deacetylpaclitaxel and paclitaxel in rat plasma was established.Approximating 500ng/mL 7-xylosyl-10-deacetylpaclitaxel was first time determinated in rats plasma after v.i.administration of 2.5mg/kg 7-xylosyl- 10-deacetylpaclitaxel.
3.Antitumor activity of 7-xylosyl-10-deacetylpaclitaxel was first time determinated in MCF-7、A549、CEM、PC-3 human cancer cells through MTT method.And PC-3 human prostate cancer cells were sensitive to 7-xylosyl-10-deacetylpaclitaxel(48h IC_(50):5μM,72h IC_(50):586nM).
4.We first time discovered that 7-xylosyl-10-deacetylpaclitaxel induced PC-3 human prostate cancer cells apoptosis as measured by flow cytometry,DNA laddering,laser confocal microscopy、transmission electron microscopy and atomic force microscopy.
5.We first time discovered that pathway of 7-xylosyl-10-deacetylpaclitaxel-triggered apoptosis in PC-3 human prostate cancer cells:
an up-regulation of pro-apoptotic Bax and Bad protein expression and a down-regulation of anti-apoptotic Bcl-2 and Bcl-X_L expression,which lead to a disturbance of the mitochondrial membrane permeability and to the activation of caspase-9.In turn, caspase-9 activated downstream caspases-3 and -6,but not caspase-8.Bid was also activated by caspase-3.Reversely,treatment with a caspase-10-specific inhibitor could not protect PC-3 cells from 7-xylosyl-10-deacetylpaclitaxel-triggered apoptosis. Moreover,7-xylosyl-10-deacetylpaclitaxel had no effect on the expression of CD95 and NF-κB proteins,indicating that apoptosis was induced through the mitochondrial-dependent pathway in PC-3 cells.
The pathway of 7-xylosyl-10-deacetylpaclitaxel-triggered apoptosis was different to the pathway of paclitaxel-triggered apoptosis.
In summary,Systematic study on antitumor activity and mechanism of 7-xylosyl-10 -deacetylpaclitaxel established substantial basis to develop new drug.
引文
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