菲并吲哚里西啶类生物碱13a-（S）-去氧娃儿藤宁的抗肿瘤作用及机制研究
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摘要
菲并吲哚里西啶类生物碱是一类植物来源的小分子化合物,具有多种药理学活性。其结构母核完全不同于已上市的任何一种抗肿瘤药物。这类生物碱的生物学作用广泛,包括抗肿瘤作用、抗炎作用、抗阿米巴虫作用和抗病毒作用等。菲并吲哚里西啶类生物碱抗肿瘤作用瘤谱和其特异性的分子靶标尚不清楚。为此,本文对其抗肿瘤作用及其作用机制进行了较详尽地研究。
右旋去氧娃儿藤宁((+)-13 a-(S)-Deoxytylophorinine,简称CAT)是最早从萝藦科(Asclepiadaceae)娃儿藤属(Tylophora)的植物三分丹(Tylophora atrofolliculata)和卵叶娃儿藤(Tylophora ovata)中提取出的菲并吲哚里西啶类化合物,因其植物中含量很低,来源有限,因此,对该化合物进行了化学全合成。
我们首先检测了该化合物的体外和体内的抗肿瘤作用。该化合物及其多种结构衍生物在体外对多种组织细胞来源的肿瘤细胞具有良好的抗肿瘤作用,ICso在10-7-10-8mol/L的范围内。小鼠体内移植瘤实验表明,该化合物的多种给药方案均能够显著地抑制移植肿瘤的生长。
由于该化合物的水溶性较差,为改善其溶解性,将其制成了马来酸盐、枸橼酸盐和酒石酸盐等多种盐。体外和体内的药效学研究表明,该化合物的体内外抗肿瘤作用与原型化合物相当或相近。以往的CAT原型化合物只能用羧甲基纤维素钠溶液制成悬液口服给药。成盐后,可注射给予。但由于该药的血管刺激性较强,动物耐受性较差,因此静脉注射给药的效果不佳。
药动学上考察了该化合物在血液和脑组织中分布的情况。CAT及其盐给药后,可以透过血脑屏障,进入脑组织。口服给药后5min,脑组织中即可检测到原型化合物。给药后15min,脑组织中出现分布高峰,给药后2h,脑组织中仍能维持一定的药物水平。可见CAT可以透过血脑屏障进入脑组织。这一特性是该化合物的一大优点,这使得该化合物有可能用于治疗脑肿瘤。多数现有的细胞毒类的抗肿瘤药物都是注射给药,可以口服给药的相对较少,而能够口服给药并能够透过血脑屏障进入到脑组织,可治疗脑肿瘤的抗肿瘤药则更少。
有文献报道,一些菲并吲哚里西啶类化合物具有神经毒性。为此我们对CAT的神经毒性进行了初步的评价,以考察该化合物是否有神经毒性及出现神经毒性的程度。我们采用大鼠嗜铬细胞瘤PC-12细胞神经突触生长试验进行评价,该试验可初步预测化合物的神经毒性。结果发现,与具有神经毒性的已经上市的抗肿瘤药物长春新碱相比,CAT基本不影响大鼠嗜铬细胞瘤PC-12细胞的神经突触的生长,因此提示,所用剂量范围内CAT无明显的神经毒性。
针对已有的报道和我们实验室前期的研究工作,我们推测菲并吲哚里西啶类化合物CAT可能与核酸(包括DNA和RNA)存在某种相互作用,而核酸本身很可能就是这类药物的重要靶点。因此,我们在实验中对CAT与核酸的相互作用进行了细致地研究。采用圆二色谱法和荧光发射光谱法进行了检测,发现CAT与CT-DNA之间具有直接的、浓度依赖性的相互作用。并且,这种相互作用具有序列特异性。CAT偏好结合富含AT重复序列的DNA片段。以放线菌素D作为阳性对照,应用圆二色谱法检测了四种8bp寡核苷酸序列与CAT的相互作用,发现CAT偏好结合AT重复序列。我们进一步地将8bp序列延长到12bp和20bp,又进一步地证实了这种AT偏好结合的相互作用。我们又采用荧光发射光谱法对这四条8bp寡核苷酸序列与CAT的相互作用进行了检测,结果也证实了这一序列特异性的相互作用。进一步采用14种富含AT序列和缺乏AT的序列进行圆二色谱法及荧光发射光谱法的检测。检测结果也进一步得到证实,CAT与DNA相互作用的AT序列特异性。而且这种相互作用又进一步地被采用DNA粘度检测法证明为嵌入式的相互作用。我们的实验数据还显示CAT与RNA也具有直接的、浓度依赖性的相互作用。
CAT的对映异构体-CAT与+CAT仅相差一个手性碳原子的构型,但是体内外活性却相差甚远。我们进一步地采用基因芯片技术和蛋白质组学的方法考察了去氧娃儿藤宁的两个对映异构体对人神经胶质瘤U251细胞的基因表达谱和蛋白表达谱影响的差异。结果发现,差异基因中包含有常规的与细胞凋亡、细胞周期调节、细胞信号转导、细胞生长调节等相关基因。此外,还包括相当多的与DNA复制和损伤修复、转录起始复合物和转录调节及核糖体翻译等相关基因。这些基因的变化与我们前期证明的+CAT能够序列特异性地嵌入到DNA的碱基对之间,以及能够与核糖体RNA直接地相互作用有关。通过蛋白质组学的技术方法找到了一些差异表达的蛋白,这些蛋白与细胞生长和分化调节、分子伴侣、激酶、细胞组成蛋白、能量代谢调节等多种功能有关。
总之,CAT作为全新结构母核、作用机制与众不同、植物来源的抗肿瘤新型化合物,具有良好的开发前景。CAT脂溶性好,可口服给药,并可透过血脑屏障,且没有明显的神经毒性。因此,CAT有望开发成为口服治疗脑肿瘤的新型药物。
Phenanthroindolizidine alkaloids are a family of plant-derived compounds with various pharmacological activities. Its chemical structure is different from any known anticancer drugs. Phenanthroindolizidine alkaloid exhibits many biological activities, including anticancer, antiinfiamatory, anti-ameobicidal and anti-viral activities. Specific biomolecular targets of this kind of alkaloids have not yet been clearly identified. (+)-13a-(S)-Deoxytylophorinine (short for CAT) is a new phenanthroindolizidine alkaloid, originally extracted from the roots of Tylophora atrofolliculata and Tylophora ovata, which are from family of Asclepiadaceae. Its content from plant is very low. The total synthesis of this compound resolved the major problem of its low natural availability.
At first, we tested the in vitro and in vivo anticancer activities of this compound and some of its derivatives. They exhibited favorable anticancer activities in many cancer cells from different tissue origins, with IC50 in the range of 10-7-10-8mol/L. In mouse xenograft model, CAT and its salts, in several dosage regimen, can well inhibit the growth of transplanted tumors.
CAT's solubility in water is rather poor. In order to improve its water solubility, several salts of CAT were made, including malate, citrate and tartrate. In vitro and in vivo evaluations proved that the salts of CAT are equivalent to CAT in its anticancer activities. CAT can be administrated p.o. in CMC suspensions, while the salts can also be administrated i.v. However, due to the severe vescular irritation, the tolerance to animals is rather poor, the effects of intravenous administration were not better.
The distributions of CAT in blood and brain tissues are also tested. CAT and its salts can come into brain through brain blood barrier.5min after oral administration, CAT can be detected in brain and it comes to its peak concentration after 15min.2 hours later, the concentration of CAT can still be maintained in certain concentration level. So, this proves that CAT can penetrate blood brain barrier and may be used to treat brain tumor by oral administrations.
Several compounds from phenanthroindolizidine alkaloid family were reported to exhibit severe neurotoxicity. We also preliminarily evaluated the neurotoxicity of CAT by rat pheochromocytoma PC 12 cell neurite-outgrowth assay which is a dependable model for predicting neurotoxicity in vitro. Compared to vincristinine, an anticancer drug with severe neurotoxicity, CAT exerts no neurotoxicity even at relatively high concentrations.
Interactions between this compound and DNA sequences were studied in details with circular dichroic spectroscopy and Fluorescence spectroscopy. Concentration-dependent interactions were observed and this compound seemed to interact sequence-specifically with AT-repeated sequence of double-helical DNA. Such interactions were proved to be intercalating rather than groove binding by viscosity measurements. Interactions between CAT and RNA were also tested, and concentration-dependent interactions were observed.
The enantiomer of CAT,-CAT, has only one different chiral carbon atom with CAT. However,-CAT's in vitro and in vivo anticancer activities were far inferior to its enantiomer. We further userd gene chip and proteomic technology to detect the discrepancy of gene expression profile and protein expression profile of human glioma U251 cells, treated by CAT and its enantiomer. Several genes related to apoptosis, cell cycle regulation, signaling transduction and growth regulation as well as genes related to DNA replication, reparation, transcription regulation and ribosome translation were found upregulated or downregulated after the treatment of CAT, rather than its enantiomer. We also find several proteins by proteomic technology that expressed differentially after the treatment of CAT and its enantiomer.
In short, CAT was a novel plant-derived anticancer alkaloid of distinct mechanisms, with broad perspect for further development. CAT can be orally administrated and can penetrate the blood brain barrier without obvious neurotoxicity. CAT or its derivatives can well be developed into a new anticancer drug for glioma or other brain cancers.
右旋去氧娃儿藤宁((+)-13 a-(S)-Deoxytylophorinine,简称CAT)是最早从萝藦科(Asclepiadaceae)娃儿藤属(Tylophora)的植物三分丹(Tylophora atrofolliculata)和卵叶娃儿藤(Tylophora ovata)中提取出的菲并吲哚里西啶类化合物,因其植物中含量很低,来源有限,因此,对该化合物进行了化学全合成。
我们首先检测了该化合物的体外和体内的抗肿瘤作用。该化合物及其多种结构衍生物在体外对多种组织细胞来源的肿瘤细胞具有良好的抗肿瘤作用,ICso在10-7-10-8mol/L的范围内。小鼠体内移植瘤实验表明,该化合物的多种给药方案均能够显著地抑制移植肿瘤的生长。
由于该化合物的水溶性较差,为改善其溶解性,将其制成了马来酸盐、枸橼酸盐和酒石酸盐等多种盐。体外和体内的药效学研究表明,该化合物的体内外抗肿瘤作用与原型化合物相当或相近。以往的CAT原型化合物只能用羧甲基纤维素钠溶液制成悬液口服给药。成盐后,可注射给予。但由于该药的血管刺激性较强,动物耐受性较差,因此静脉注射给药的效果不佳。
药动学上考察了该化合物在血液和脑组织中分布的情况。CAT及其盐给药后,可以透过血脑屏障,进入脑组织。口服给药后5min,脑组织中即可检测到原型化合物。给药后15min,脑组织中出现分布高峰,给药后2h,脑组织中仍能维持一定的药物水平。可见CAT可以透过血脑屏障进入脑组织。这一特性是该化合物的一大优点,这使得该化合物有可能用于治疗脑肿瘤。多数现有的细胞毒类的抗肿瘤药物都是注射给药,可以口服给药的相对较少,而能够口服给药并能够透过血脑屏障进入到脑组织,可治疗脑肿瘤的抗肿瘤药则更少。
有文献报道,一些菲并吲哚里西啶类化合物具有神经毒性。为此我们对CAT的神经毒性进行了初步的评价,以考察该化合物是否有神经毒性及出现神经毒性的程度。我们采用大鼠嗜铬细胞瘤PC-12细胞神经突触生长试验进行评价,该试验可初步预测化合物的神经毒性。结果发现,与具有神经毒性的已经上市的抗肿瘤药物长春新碱相比,CAT基本不影响大鼠嗜铬细胞瘤PC-12细胞的神经突触的生长,因此提示,所用剂量范围内CAT无明显的神经毒性。
针对已有的报道和我们实验室前期的研究工作,我们推测菲并吲哚里西啶类化合物CAT可能与核酸(包括DNA和RNA)存在某种相互作用,而核酸本身很可能就是这类药物的重要靶点。因此,我们在实验中对CAT与核酸的相互作用进行了细致地研究。采用圆二色谱法和荧光发射光谱法进行了检测,发现CAT与CT-DNA之间具有直接的、浓度依赖性的相互作用。并且,这种相互作用具有序列特异性。CAT偏好结合富含AT重复序列的DNA片段。以放线菌素D作为阳性对照,应用圆二色谱法检测了四种8bp寡核苷酸序列与CAT的相互作用,发现CAT偏好结合AT重复序列。我们进一步地将8bp序列延长到12bp和20bp,又进一步地证实了这种AT偏好结合的相互作用。我们又采用荧光发射光谱法对这四条8bp寡核苷酸序列与CAT的相互作用进行了检测,结果也证实了这一序列特异性的相互作用。进一步采用14种富含AT序列和缺乏AT的序列进行圆二色谱法及荧光发射光谱法的检测。检测结果也进一步得到证实,CAT与DNA相互作用的AT序列特异性。而且这种相互作用又进一步地被采用DNA粘度检测法证明为嵌入式的相互作用。我们的实验数据还显示CAT与RNA也具有直接的、浓度依赖性的相互作用。
CAT的对映异构体-CAT与+CAT仅相差一个手性碳原子的构型,但是体内外活性却相差甚远。我们进一步地采用基因芯片技术和蛋白质组学的方法考察了去氧娃儿藤宁的两个对映异构体对人神经胶质瘤U251细胞的基因表达谱和蛋白表达谱影响的差异。结果发现,差异基因中包含有常规的与细胞凋亡、细胞周期调节、细胞信号转导、细胞生长调节等相关基因。此外,还包括相当多的与DNA复制和损伤修复、转录起始复合物和转录调节及核糖体翻译等相关基因。这些基因的变化与我们前期证明的+CAT能够序列特异性地嵌入到DNA的碱基对之间,以及能够与核糖体RNA直接地相互作用有关。通过蛋白质组学的技术方法找到了一些差异表达的蛋白,这些蛋白与细胞生长和分化调节、分子伴侣、激酶、细胞组成蛋白、能量代谢调节等多种功能有关。
总之,CAT作为全新结构母核、作用机制与众不同、植物来源的抗肿瘤新型化合物,具有良好的开发前景。CAT脂溶性好,可口服给药,并可透过血脑屏障,且没有明显的神经毒性。因此,CAT有望开发成为口服治疗脑肿瘤的新型药物。
Phenanthroindolizidine alkaloids are a family of plant-derived compounds with various pharmacological activities. Its chemical structure is different from any known anticancer drugs. Phenanthroindolizidine alkaloid exhibits many biological activities, including anticancer, antiinfiamatory, anti-ameobicidal and anti-viral activities. Specific biomolecular targets of this kind of alkaloids have not yet been clearly identified. (+)-13a-(S)-Deoxytylophorinine (short for CAT) is a new phenanthroindolizidine alkaloid, originally extracted from the roots of Tylophora atrofolliculata and Tylophora ovata, which are from family of Asclepiadaceae. Its content from plant is very low. The total synthesis of this compound resolved the major problem of its low natural availability.
At first, we tested the in vitro and in vivo anticancer activities of this compound and some of its derivatives. They exhibited favorable anticancer activities in many cancer cells from different tissue origins, with IC50 in the range of 10-7-10-8mol/L. In mouse xenograft model, CAT and its salts, in several dosage regimen, can well inhibit the growth of transplanted tumors.
CAT's solubility in water is rather poor. In order to improve its water solubility, several salts of CAT were made, including malate, citrate and tartrate. In vitro and in vivo evaluations proved that the salts of CAT are equivalent to CAT in its anticancer activities. CAT can be administrated p.o. in CMC suspensions, while the salts can also be administrated i.v. However, due to the severe vescular irritation, the tolerance to animals is rather poor, the effects of intravenous administration were not better.
The distributions of CAT in blood and brain tissues are also tested. CAT and its salts can come into brain through brain blood barrier.5min after oral administration, CAT can be detected in brain and it comes to its peak concentration after 15min.2 hours later, the concentration of CAT can still be maintained in certain concentration level. So, this proves that CAT can penetrate blood brain barrier and may be used to treat brain tumor by oral administrations.
Several compounds from phenanthroindolizidine alkaloid family were reported to exhibit severe neurotoxicity. We also preliminarily evaluated the neurotoxicity of CAT by rat pheochromocytoma PC 12 cell neurite-outgrowth assay which is a dependable model for predicting neurotoxicity in vitro. Compared to vincristinine, an anticancer drug with severe neurotoxicity, CAT exerts no neurotoxicity even at relatively high concentrations.
Interactions between this compound and DNA sequences were studied in details with circular dichroic spectroscopy and Fluorescence spectroscopy. Concentration-dependent interactions were observed and this compound seemed to interact sequence-specifically with AT-repeated sequence of double-helical DNA. Such interactions were proved to be intercalating rather than groove binding by viscosity measurements. Interactions between CAT and RNA were also tested, and concentration-dependent interactions were observed.
The enantiomer of CAT,-CAT, has only one different chiral carbon atom with CAT. However,-CAT's in vitro and in vivo anticancer activities were far inferior to its enantiomer. We further userd gene chip and proteomic technology to detect the discrepancy of gene expression profile and protein expression profile of human glioma U251 cells, treated by CAT and its enantiomer. Several genes related to apoptosis, cell cycle regulation, signaling transduction and growth regulation as well as genes related to DNA replication, reparation, transcription regulation and ribosome translation were found upregulated or downregulated after the treatment of CAT, rather than its enantiomer. We also find several proteins by proteomic technology that expressed differentially after the treatment of CAT and its enantiomer.
In short, CAT was a novel plant-derived anticancer alkaloid of distinct mechanisms, with broad perspect for further development. CAT can be orally administrated and can penetrate the blood brain barrier without obvious neurotoxicity. CAT or its derivatives can well be developed into a new anticancer drug for glioma or other brain cancers.
引文
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