多孔菌抗肿瘤活性评价及巨多孔菌有效成分分离、结构鉴定及诱导HeLa细胞凋亡的分子机理研究
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摘要
多孔菌是属于担子菌亚门的一类大型真菌，它们与子囊菌亚门的一些种共同构成了高等真菌药用活性物质的主要来源。为了开发利用我国的多孔菌资源，本论文对多孔菌进行了以下研究：
1、对浙江、湖南两省的药用多孔菌资源进行了调查、采集、鉴定，并采用MTT法详细评价了35种多孔菌对人宫颈癌细胞株HeLa及人肝癌细胞株SMMC-7721的体外抗肿瘤活性。结果表明，所有参试材料的甲醇和水提取物均未显示细胞毒性(IC_(50)＞100μg／ml)，但有21种多孔菌子实体的石油醚和乙酸乙酯提取物显示了不同强度的体外抗肿瘤活性(34＜IC_(50)＜100μg／ml)，占测试材料总数的60％，其中，8种多孔菌表现了强烈的活性(IC_(50)＜50μg／ml)。选定活性最强的巨多孔菌(IC_(50)=34.2μg／ml)作为进一步研究的对象。
2、研究了巨多孔菌的生物学特性。结果显示，巨多孔菌实体的发生对土壤肥力要求不高，但是与降雨关系密切；适宜子实体生长的土壤湿度为40％-60％，光照以散射光为宜。对巨多孔菌生物学特性的了解有助于我们对该种进行引种和驯化。
3、用活性跟踪分离的方法，对巨多孔菌乙酸乙酯提取物的化学成分进行了有目的分离，得到一个具较强细胞毒活性的单体clitocine；另外，还鉴定了clitocine的一个无活性构象异构体a-clitocine。本研究首次报道的clitocine是巨多孔菌中的主要细胞毒活性物质。a-clitocine首次以天然产物的形式被报道。
4、评价了clitocine的体内、外抗肿瘤活性。结果表明，clitocine对体外培养的人宫颈癌细胞HeLa、人肝癌SMMC-772l、人乳腺癌Bcap-37和MCF-7、人胃癌细胞株SGC-7901均有增殖抑制作用，并具有一定选择性，对SMMC-7721的抑制作用最强(IC_(50)=1.1μM)，对MCF-7的作用较弱(IC_(50)=43.0μM)。小鼠体内抗肿瘤实验显示，clitocine对小鼠S180肉瘤没有显著抑制作用。首次发现clitocine对小鼠天然免疫器官—脾脏具有强烈的抑制作用。
5、首次探讨了clitocine诱导人宫颈癌细胞HeLa死亡的作用机理，获得了一些有意义的发现。15μM clitocine作用HeLa细胞诱导了时间依赖的凋亡；Clitocine诱导的细胞死亡具有典型的凋亡特征，如核形态的变化，DNA片断的产生，caspase的激活，PARP裂解，细胞色素c释放等；Clitocine处理激活了caspase-3、8、9，在48h内caspase家族抑制剂(Z-VAD-FMK)，caspase-3抑制剂(Z-DEVD-FMK)，caspase-9 inhibitor(Z-LEHD-FMK)均可显著抑制clitocine诱导的死亡；Clitocine可明显上调促凋亡蛋白Bax的表达，同时下调抗凋亡蛋白Bcl-2的表达。研究还表明clitocine诱导的HeLa细胞死亡发生在细胞周期各个时期，对周期无阻滞作用。因此，初步认为，clitocine诱导的细胞死亡是由caspase家族和Bcl-2家族共同调控，对细胞周期循环无阻滞作用的细胞凋亡过程的结果。
Polypores are a large group of terrestrial fungi of the phylum Basdiomycota (basidiomycetes), and they along with certain Ascomycota are a major source of pharmacologically active substances. In a program aim to search for antitumor substances from high fungi, the followed work were finished.
Firstly, the fruit bodies of 35 polypores from Zhejiang and Hunan Province were screed for the cytotoxic activity against human tumor cell lines by MTT dye assay. The results indicated that the most of lipid extracts including petrol ether and ethyl acetate extracts have significant cytotoxicity (34100μg/ml) . It was found that out of 35 species screened 21 exhibited cytotoxic activity. More than 60% of screened crude extracts of sample showed cytotoxicity while 8 species displayed strong cytotoxic active with IC_(50) value of less than 50 (μg/ml. Among them, the ethyl acetate extract of Grifola gigantea (Pers.) Karst exhibited the most strongest cytotoxic active against HeLa with an IC_(50) value of 34.2μg/ml.
Secondly, the biological characteristics of Grifola gigantea has been observed and main conclusion can be summarized as follows: The occurrence of sporophore are closely related to moisture. The soil with a humidity value of 40-60% and scatter light can be benefit to development of sporophore. It can produce sporophore in both fertilizer-rich and fertilizer-poor soil. The accumulation of biological knowledge may be helpful to introduction and acclimation of this fungus.
Thirdly, a bioassay-guided fractionation of the ethyl acetate extract of Grifola gigantea led to the isolation of two compound. Their structure were identified as clitocine and a-clitocine by spectra methods. Herein, clitocine with strong cytotoxicity (IC_(50)=14.9μM) was clarified as the substance responsible to the cytotoxicity of Grifola gigantea for the first time, a-clitocine, as a side-product of this chromatographic separation procedure, was reported as a natural product for the first time in this paper and was inactive though as a anomer of clitocine.
Fourthly, the antitumor active of clitocine in vitro and in vivo was evaluated using MTT method and S180 solid tumor model, respectively. Result showed that clitocine can significantly inhibit the proliferation of five human tumor cell lines including HeLa (14.9μM), SMMC-7721 (1.1μM), SGC-7901 (2.2μM), MCF-7 (43.0μM), and Bcap-37 (10.9μM). The value of IC50 indicated the cytotoxicity of clitocine against human cell lines may be of selective. Clitocine could not prevent solid tumor growth whenever rat were administered with high, medium and low doses. Furthermore, clitocine-induced immunosuppression effect on spleen was observed for the first time.
Fifthly, the molecular mechanism of clitocine-induced cytotoxicity against HeLa was investigated for the first time in this thesis and many interesting results were included. Concentration of 15μM clitocine caused the induction of apoptosis in a time dependent manner. Clitocine-induced cell death was characterized with the changes in nuclear morphology, DNA fragmentation, activation of caspase like activities, poly (ADP-ribose) polymerase cleavage, release of cytochrome c into cytosol. Clitocine activated various caspase such as caspase-3, 8, 9. Moreover, the cell death can be significantly prevented by a family caspase inhibitor (Z-VAD-FMK), caspase-3 inhibitor (Z-DEVD-FMK), caspase-9 inhibitor (Z-LEHD-FMK). Furthermore, elevated anti-apoptotic protein Bcl-2 levels and low promote-apoptotic protein Bax expression have also been detected by Western blot assay in clitocine treated cells; Clitocine had no influence on cell cycle in HeLa cells, and cltocine-induced cell death appeared at all of cell cycle phases. The overall results suggest that the progression of cell death induced by clitocine was mediated by both caspase family and Bcl-2 family and was not associated with disruption of cell cycle.
1、对浙江、湖南两省的药用多孔菌资源进行了调查、采集、鉴定，并采用MTT法详细评价了35种多孔菌对人宫颈癌细胞株HeLa及人肝癌细胞株SMMC-7721的体外抗肿瘤活性。结果表明，所有参试材料的甲醇和水提取物均未显示细胞毒性(IC_(50)＞100μg／ml)，但有21种多孔菌子实体的石油醚和乙酸乙酯提取物显示了不同强度的体外抗肿瘤活性(34＜IC_(50)＜100μg／ml)，占测试材料总数的60％，其中，8种多孔菌表现了强烈的活性(IC_(50)＜50μg／ml)。选定活性最强的巨多孔菌(IC_(50)=34.2μg／ml)作为进一步研究的对象。
2、研究了巨多孔菌的生物学特性。结果显示，巨多孔菌实体的发生对土壤肥力要求不高，但是与降雨关系密切；适宜子实体生长的土壤湿度为40％-60％，光照以散射光为宜。对巨多孔菌生物学特性的了解有助于我们对该种进行引种和驯化。
3、用活性跟踪分离的方法，对巨多孔菌乙酸乙酯提取物的化学成分进行了有目的分离，得到一个具较强细胞毒活性的单体clitocine；另外，还鉴定了clitocine的一个无活性构象异构体a-clitocine。本研究首次报道的clitocine是巨多孔菌中的主要细胞毒活性物质。a-clitocine首次以天然产物的形式被报道。
4、评价了clitocine的体内、外抗肿瘤活性。结果表明，clitocine对体外培养的人宫颈癌细胞HeLa、人肝癌SMMC-772l、人乳腺癌Bcap-37和MCF-7、人胃癌细胞株SGC-7901均有增殖抑制作用，并具有一定选择性，对SMMC-7721的抑制作用最强(IC_(50)=1.1μM)，对MCF-7的作用较弱(IC_(50)=43.0μM)。小鼠体内抗肿瘤实验显示，clitocine对小鼠S180肉瘤没有显著抑制作用。首次发现clitocine对小鼠天然免疫器官—脾脏具有强烈的抑制作用。
5、首次探讨了clitocine诱导人宫颈癌细胞HeLa死亡的作用机理，获得了一些有意义的发现。15μM clitocine作用HeLa细胞诱导了时间依赖的凋亡；Clitocine诱导的细胞死亡具有典型的凋亡特征，如核形态的变化，DNA片断的产生，caspase的激活，PARP裂解，细胞色素c释放等；Clitocine处理激活了caspase-3、8、9，在48h内caspase家族抑制剂(Z-VAD-FMK)，caspase-3抑制剂(Z-DEVD-FMK)，caspase-9 inhibitor(Z-LEHD-FMK)均可显著抑制clitocine诱导的死亡；Clitocine可明显上调促凋亡蛋白Bax的表达，同时下调抗凋亡蛋白Bcl-2的表达。研究还表明clitocine诱导的HeLa细胞死亡发生在细胞周期各个时期，对周期无阻滞作用。因此，初步认为，clitocine诱导的细胞死亡是由caspase家族和Bcl-2家族共同调控，对细胞周期循环无阻滞作用的细胞凋亡过程的结果。
Polypores are a large group of terrestrial fungi of the phylum Basdiomycota (basidiomycetes), and they along with certain Ascomycota are a major source of pharmacologically active substances. In a program aim to search for antitumor substances from high fungi, the followed work were finished.
Firstly, the fruit bodies of 35 polypores from Zhejiang and Hunan Province were screed for the cytotoxic activity against human tumor cell lines by MTT dye assay. The results indicated that the most of lipid extracts including petrol ether and ethyl acetate extracts have significant cytotoxicity (34
Secondly, the biological characteristics of Grifola gigantea has been observed and main conclusion can be summarized as follows: The occurrence of sporophore are closely related to moisture. The soil with a humidity value of 40-60% and scatter light can be benefit to development of sporophore. It can produce sporophore in both fertilizer-rich and fertilizer-poor soil. The accumulation of biological knowledge may be helpful to introduction and acclimation of this fungus.
Thirdly, a bioassay-guided fractionation of the ethyl acetate extract of Grifola gigantea led to the isolation of two compound. Their structure were identified as clitocine and a-clitocine by spectra methods. Herein, clitocine with strong cytotoxicity (IC_(50)=14.9μM) was clarified as the substance responsible to the cytotoxicity of Grifola gigantea for the first time, a-clitocine, as a side-product of this chromatographic separation procedure, was reported as a natural product for the first time in this paper and was inactive though as a anomer of clitocine.
Fourthly, the antitumor active of clitocine in vitro and in vivo was evaluated using MTT method and S180 solid tumor model, respectively. Result showed that clitocine can significantly inhibit the proliferation of five human tumor cell lines including HeLa (14.9μM), SMMC-7721 (1.1μM), SGC-7901 (2.2μM), MCF-7 (43.0μM), and Bcap-37 (10.9μM). The value of IC50 indicated the cytotoxicity of clitocine against human cell lines may be of selective. Clitocine could not prevent solid tumor growth whenever rat were administered with high, medium and low doses. Furthermore, clitocine-induced immunosuppression effect on spleen was observed for the first time.
Fifthly, the molecular mechanism of clitocine-induced cytotoxicity against HeLa was investigated for the first time in this thesis and many interesting results were included. Concentration of 15μM clitocine caused the induction of apoptosis in a time dependent manner. Clitocine-induced cell death was characterized with the changes in nuclear morphology, DNA fragmentation, activation of caspase like activities, poly (ADP-ribose) polymerase cleavage, release of cytochrome c into cytosol. Clitocine activated various caspase such as caspase-3, 8, 9. Moreover, the cell death can be significantly prevented by a family caspase inhibitor (Z-VAD-FMK), caspase-3 inhibitor (Z-DEVD-FMK), caspase-9 inhibitor (Z-LEHD-FMK). Furthermore, elevated anti-apoptotic protein Bcl-2 levels and low promote-apoptotic protein Bax expression have also been detected by Western blot assay in clitocine treated cells; Clitocine had no influence on cell cycle in HeLa cells, and cltocine-induced cell death appeared at all of cell cycle phases. The overall results suggest that the progression of cell death induced by clitocine was mediated by both caspase family and Bcl-2 family and was not associated with disruption of cell cycle.
引文
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