通过高通量筛选技术从中药材中发现抗黑色素瘤的新天然化合物
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摘要
黑色素瘤在最常见的癌症中排第六位,它恶性程度很高,是最危险的皮肤癌。黑色素瘤同时也是一个主要的健康问题,近年来它在世界范围内的发病率有所升高。浸润性黑色素瘤的发病率在白人中最高,几乎是其他人种发病率的30倍。在65岁及65岁以上的人群中,黑色素瘤在男性中发病的可能性要比在女性中高出2倍(在女性和男性中的发病率分别为1/35和1/25),每年发病大约有100,000例。根据世界卫生组织下属的国际癌症研究署的数据,皮肤黑色素瘤发病率最高的国家是澳大利亚和新西兰。黑色素瘤的发病率一直上升,但是用来治疗黑色素瘤的手段有限,因此死亡率也有所上升。
用来阻止黑色素瘤转移和杀死癌细胞的化疗手段包括:烷基化试剂(如氮烯咪胺,有效率在15%-20%之间),铂类药物(如顺铂,单独治疗有效率为15%左右),微管毒素药物(如紫杉醇,单独使用时有效率为16%左右),这些药物的疗效不理想和药物的副作用是化疗的主要问题。从总体疗效和存活率来看,当前转移性黑色素瘤的治疗手段还有待提高。虽然一些药物在生物化学实验中表现出了不错的结果,但是没有一种药物或者是手段能在随后的试验中提高反应的中间期和生存率。来源于植物和草药的天然产物,单独使用或者联合其他药物使用,也许会提供治疗恶性黑色素瘤的一种新的治疗方法。
天然产物一直是药物先导化合物的最成功的来源,天然产物能提供大于标准组合化学所能提供的结构多样性,天然产物也是新型的低分子量的先导结构的主要来源,这些先导化合物具有针对多个靶点的活性。中药经过了历史上千年的检验,有助于天然活性成分(尤其是用于医疗用途的活性成分)的确定,也许将推动世界范围内新药的研发。源于中药的天然产物在治疗癌症中有很大潜力,例如青蒿琥酯,高三尖杉酯碱,As2O3,斑蝥素。对照临床研究发现,高三尖杉酯碱和As2O3对治疗白血病有显著活性。对中药来源的药物的分子机制越来越多的了解及其最近在应用方面的发展证实了:中药和现代尖端科技的结合可以为发展新型和改良型抗癌药物提供非常引人注目的策略。
高通量筛选是发现有望在不久的将来用于癌症有效治疗而副作用少的天然小分子的新策略,也是加速其分离,鉴定及表征过程的新策略。在本文中,我们用高通量筛选的方法对源于500种中药的组分库的抗黑色素瘤的活性进行了初步筛选,确定了两个具有抗黑色素瘤和其他肿瘤活性的天然小分子。
我们使用基于高通量筛选的新策略来系统地针对药物靶点进行中药活性物质的筛选并确定。用于筛选的组分库由中国药典常见的500种中药构成,这些中药有各种活性成分,能够治疗包括肿瘤在内的很多疾病。为构建中药组分库,每种中药粉末用95%乙醇在索氏提取器内95°C回流提取10小时,然后用制备型高效液相色谱(HPLC)收集组分。每种中药粗提物经处理后,用10%-100%甲醇梯度洗脱(每个组分中可见峰在1-17个),收集80个组分,由此得到了来源于500种中药的适合高通量筛选的40,000个组分。假定每个组分中的各种物质的平均分子量为500道尔顿,将每个组分用DMSO溶解成20 mM溶液置于96孔板中构成直接用于筛选的组分库。有活性的单体化合物由进一步的活性引导分离得到并进行结构鉴定。
用于筛选抗黑色素瘤中药组分的终浓度为100μM。我们用A375细胞系筛选了源于240种中药的19,200个组分,其中67种中药的154个组分表现出了抑制黑色素瘤细胞生长的活性。随后我们进行了阳性组分对新鲜分离的小鼠脾细胞的毒性试验,以排除对正常细胞有毒性的组分。结果显示,110个组分具有显著的细胞毒性,44个组分没有明显的毒性。因其抗黑色素瘤活性好而且对小鼠脾细胞毒性小,艾叶被选择以分离其中具有抑制黑色素瘤活性的化合物。有机溶剂萃取和制备型HPLC收集组分被用来分离艾叶中的活性成分。最终我们从艾叶中得到两种能够抑制A375细胞增殖的化合物,通过质谱,1H NMR和13C NMR,确定其结构为O-甲基黄酮—异泽兰黄素(5,7-二羟基-3’,4’,6-三甲氧基黄酮)和棕矢车菊素(4,5,7-三羟基-3’,6-二甲氧基黄酮)。
检验异泽兰黄素对A375细胞的抑制增殖效应的MTT测试结果表明,其EC50大约为150μM。异泽兰黄素特异性地诱导A375细胞形态变化,对正常的小鼠脾细胞的毒性较小。进一步研究显示其对A375细胞生长呈现剂量依赖的抑制作用,与DNA损伤,细胞凋亡和细胞周期阻滞在G2/M期有关。异泽兰黄素诱导凋亡的效应通过Annexin V-FITC/PI双染色并由流式细胞仪进行检测得到证实。结果显示:150μM和300μM的异泽兰黄素处理的细胞凋亡率分别为13.05%和29.20%,而对照组的细胞凋亡率只有2.04%。同时我们也进行了Hoechst33258染色来检测细胞凋亡(很容易检测到细胞核中的DNA断裂)。流式细胞术检测结果显示异泽兰黄素处理引起细胞周期阻滞,浓度为150μM和300μM的药物处理细胞24h后,G2/M期的细胞由对照组的8.82%上升到21.70%和29.86%。
以上结果表明,我们使用中药组分库进行高通量筛选的策略在发现抗肿瘤的天然小分子中是行之有效的方法。两种具有抗黑色素瘤活性的黄酮类化合物值得进一步的机制和疗效研究。对本研究中发现的其它中药阳性组分中单体化合物的分离和功能鉴定,也许能有助于发现新的药物作用机制以及高活性的抗黑色素瘤新药。
Melanoma is the sixth most common cancer and the malignancy with the highest rise in incidence and the most dangerous form of skin cancer. Melanoma is also a major health problem and its rates are increasing in the worldwide. The incidence rate for invasive melanoma is highest in whites, who are almost 30 times more likely to develop melanoma. Men aged 65 or older are more than twice as likely to develop melanoma as women in the same age group (The Lifetime risk for Melanoma is 1 in 35 women and 1 in 25 men) and number of cases is about 100,000 per year. According to the International Agency for Research on Cancer, the countries with the highest incidence of cutaneous melanoma are Australia and New Zealand. The incidence of melanoma is increasing, and the therapeutic options for malignant disease are limited, resulting in an increase in the death rate.
The chemotherapy of melanoma is to prevent the metastasis and kill the cancer cells which is including Alkylating Agents (such Dacarbazine (DTIC), response rate is 15% to 20%), Platinum Drugs (such cisplatin, response of 15% as a single treatment) and Microtubule-toxin Agents (such paclitaxel, response rate of 16% as single treatment) and still the side effects are main problem of chemotherapy agents. The current treatment for metastatic melanoma is still poor in overall response and survival rate. Although some bio-chemotherapy trials have shown good outcomes, no agent or regimen has improved median response duration and overall survival in subsequent studies. New treatment options, as single or in combination, with the use of natural phyto-compounds or herbal medicines may provide new agents in the treatment of malignant melanoma.
The natural products are the most consistently successful source of drug leads and provide a greater structural diversity than standard combinatorial chemistry and offer major opportunities for finding novel low molecular weight lead structures that are active against a wide range of assay targets. Traditional Chinese Medicine (TCM) has been practiced for thousands of years with a long history of 2000 to 3000 years and has contributed in the worldwide to the identification of active ingredients for a particular medical usage for several TCM composed of single or multiple herbal components.
In the coming years, the stage is set for a more systematic, rigorous analysis and testing of therapeutic agents used in TCM that may eventually lead to the development of useful therapeutic agents for the entire world. TCM natural products have the potential for use in cancer therapy, for example; artesunate, homoharringtonine, arsenic trioxide and cantharidin, the controlled clinical studies have shown that homoharringtonine and arsenic trioxide can exert profound activity against leukaemia. Increased knowledge of the molecular mechanisms of TCM-derived drugs and recent developments in their applications demonstrate that the combination of TCM with modern cutting-edge technologies provides an attractive strategy for the development of novel and improved cancer therapeutics.
Furthermore, high throughput screening is a new development of strategy to speed up the identification, isolation and characterization process and to discover small natural molecules that can be delivered to use in cancer treatment with less side effects on the human health in the near future. In the present study, we used high throughput screening approaches to investigate the melanoma properties of a compounds fraction library from 500 Chinese herbs and to identify new small natural molecules with anticancer properties against melanoma and other cancer cells.
We have developed a novel HTS-based strategy to systematically identify active natural compounds against any drug target from Chinese medicinal herbs. An herbal compound fraction library was constructed from 500 herbs most frequently used in Traditional Chinese Medicine (TCM) that are likely to contain therapeutic ingredients for a broad spectrum of human diseases including virus infection. For construction of the TCM fraction library, crude herbal extracts were first prepared by 95% ethanol extraction on Soxhlet reflux apparatus followed by automated fractionation of the extracts using preparative HPLC. Eighty fractions were collected from each herb by 0-90% methanol gradient. The number of single compounds in each fraction was ranging from 1 to 17 (averaged 10.4). We have built up a natural compounds library with 40,000 fractions from 500 herbs that is suitable for high throughput screening. Single active compounds from positive fractions are identified by further fractionation, activity analysis and structure determination. For high throughput screening, a working TCM fraction library was prepared in 96-well format by dissolving each fraction in DMSO to make a 20 mM solution suppose average compounds molecular weight is 500 dolton.
A final concentration of 100μM was used to screen for anti-melanoma activity. Among 240 Chinese herbs containing 19,200 fractions screened against human melanoma cancer cell line A375, we identified 154 positive fractions from 67 herbs. We tested the toxicity of positive fractions on freshly isolated mouse splenocytes to exclude fractions toxic to normal cells. The results indicated 110 fractions with remarkable toxicity and 44 fractions with no significant effect on mouse splenocytes. We choose a positive fraction with anti-melanoma activity and least toxicity on splenocytes from a Chinese herb called Artemisia Argyi to isolate positive single compounds that are responsible for the anti-melanoma activity. Organic extraction followed by preparative HPLC fractionation was used to isolate anti-melanoma single compounds from herbal plant Artemisia Argyi. We have successfully isolated two compounds with anti-proliferative effect on A375 melanoma cells. The chemical structures of the two compounds were determined as an O-methylated flavone; Eupatilin (5, 7-dihydroxy-3', 4’, 6-trimethoxyflavone) and jaceosidin (4, 5, 7-trihydroxy-3', 6-dimethoxyflavone) by using MS, 1H NMR and 13C NMR.
The anti-proliferative effect of eupatilin in human melanoma A375 cells was performed by MTT assay. The EC50 value is about 150μM. Eupatilin specifically induced morphological changes in A375 cells and was less toxic to the normal mouse splenocytes. The inhibitory effects of A375 cells were associated with the DNA damage, apoptosis, and cell cycle arrest at G2/M phase in a dose-dependent manner. The apoptotic effects of eupatilin were further verified by using Annexin V-FITC/propidium iodide staining in flow cytometry. It was observed that the apoptosis rates were 13.05% and 29.2% in A375 cells treated with 150 and 300μM eupatilin for 24 h, respectively, compared to the control cells at 2.04%. Furthermore we indicated apoptosis effect by using Hoechst staining (easily detect the fragmentation of DNA in cell nucleus). Flow cytometry was performed to determine whether eupatilin induced cell cycle arrest. The percentage of A375 cells in G2/M phase was increased from 8.82% in untreated cells to 21.70%, and 29.86% in the cells treated for 24h with 150 and 300μM eupatilin, respectively.
These results suggest that our high throughput screening strategy using herbal fraction library is promising in identifying small natural molecules with anti-melanoma activity. The two identified flavones compounds with confirmed anti-melanoma activity perhaps worth further mechanistic and therapeutic studies in human melanoma. Isolation and functional characterization of single compounds from other positive fraction of different herbs may identify new natural compounds with new mechanisms and ideal therapeutic properties against human melanoma.
用来阻止黑色素瘤转移和杀死癌细胞的化疗手段包括:烷基化试剂(如氮烯咪胺,有效率在15%-20%之间),铂类药物(如顺铂,单独治疗有效率为15%左右),微管毒素药物(如紫杉醇,单独使用时有效率为16%左右),这些药物的疗效不理想和药物的副作用是化疗的主要问题。从总体疗效和存活率来看,当前转移性黑色素瘤的治疗手段还有待提高。虽然一些药物在生物化学实验中表现出了不错的结果,但是没有一种药物或者是手段能在随后的试验中提高反应的中间期和生存率。来源于植物和草药的天然产物,单独使用或者联合其他药物使用,也许会提供治疗恶性黑色素瘤的一种新的治疗方法。
天然产物一直是药物先导化合物的最成功的来源,天然产物能提供大于标准组合化学所能提供的结构多样性,天然产物也是新型的低分子量的先导结构的主要来源,这些先导化合物具有针对多个靶点的活性。中药经过了历史上千年的检验,有助于天然活性成分(尤其是用于医疗用途的活性成分)的确定,也许将推动世界范围内新药的研发。源于中药的天然产物在治疗癌症中有很大潜力,例如青蒿琥酯,高三尖杉酯碱,As2O3,斑蝥素。对照临床研究发现,高三尖杉酯碱和As2O3对治疗白血病有显著活性。对中药来源的药物的分子机制越来越多的了解及其最近在应用方面的发展证实了:中药和现代尖端科技的结合可以为发展新型和改良型抗癌药物提供非常引人注目的策略。
高通量筛选是发现有望在不久的将来用于癌症有效治疗而副作用少的天然小分子的新策略,也是加速其分离,鉴定及表征过程的新策略。在本文中,我们用高通量筛选的方法对源于500种中药的组分库的抗黑色素瘤的活性进行了初步筛选,确定了两个具有抗黑色素瘤和其他肿瘤活性的天然小分子。
我们使用基于高通量筛选的新策略来系统地针对药物靶点进行中药活性物质的筛选并确定。用于筛选的组分库由中国药典常见的500种中药构成,这些中药有各种活性成分,能够治疗包括肿瘤在内的很多疾病。为构建中药组分库,每种中药粉末用95%乙醇在索氏提取器内95°C回流提取10小时,然后用制备型高效液相色谱(HPLC)收集组分。每种中药粗提物经处理后,用10%-100%甲醇梯度洗脱(每个组分中可见峰在1-17个),收集80个组分,由此得到了来源于500种中药的适合高通量筛选的40,000个组分。假定每个组分中的各种物质的平均分子量为500道尔顿,将每个组分用DMSO溶解成20 mM溶液置于96孔板中构成直接用于筛选的组分库。有活性的单体化合物由进一步的活性引导分离得到并进行结构鉴定。
用于筛选抗黑色素瘤中药组分的终浓度为100μM。我们用A375细胞系筛选了源于240种中药的19,200个组分,其中67种中药的154个组分表现出了抑制黑色素瘤细胞生长的活性。随后我们进行了阳性组分对新鲜分离的小鼠脾细胞的毒性试验,以排除对正常细胞有毒性的组分。结果显示,110个组分具有显著的细胞毒性,44个组分没有明显的毒性。因其抗黑色素瘤活性好而且对小鼠脾细胞毒性小,艾叶被选择以分离其中具有抑制黑色素瘤活性的化合物。有机溶剂萃取和制备型HPLC收集组分被用来分离艾叶中的活性成分。最终我们从艾叶中得到两种能够抑制A375细胞增殖的化合物,通过质谱,1H NMR和13C NMR,确定其结构为O-甲基黄酮—异泽兰黄素(5,7-二羟基-3’,4’,6-三甲氧基黄酮)和棕矢车菊素(4,5,7-三羟基-3’,6-二甲氧基黄酮)。
检验异泽兰黄素对A375细胞的抑制增殖效应的MTT测试结果表明,其EC50大约为150μM。异泽兰黄素特异性地诱导A375细胞形态变化,对正常的小鼠脾细胞的毒性较小。进一步研究显示其对A375细胞生长呈现剂量依赖的抑制作用,与DNA损伤,细胞凋亡和细胞周期阻滞在G2/M期有关。异泽兰黄素诱导凋亡的效应通过Annexin V-FITC/PI双染色并由流式细胞仪进行检测得到证实。结果显示:150μM和300μM的异泽兰黄素处理的细胞凋亡率分别为13.05%和29.20%,而对照组的细胞凋亡率只有2.04%。同时我们也进行了Hoechst33258染色来检测细胞凋亡(很容易检测到细胞核中的DNA断裂)。流式细胞术检测结果显示异泽兰黄素处理引起细胞周期阻滞,浓度为150μM和300μM的药物处理细胞24h后,G2/M期的细胞由对照组的8.82%上升到21.70%和29.86%。
以上结果表明,我们使用中药组分库进行高通量筛选的策略在发现抗肿瘤的天然小分子中是行之有效的方法。两种具有抗黑色素瘤活性的黄酮类化合物值得进一步的机制和疗效研究。对本研究中发现的其它中药阳性组分中单体化合物的分离和功能鉴定,也许能有助于发现新的药物作用机制以及高活性的抗黑色素瘤新药。
Melanoma is the sixth most common cancer and the malignancy with the highest rise in incidence and the most dangerous form of skin cancer. Melanoma is also a major health problem and its rates are increasing in the worldwide. The incidence rate for invasive melanoma is highest in whites, who are almost 30 times more likely to develop melanoma. Men aged 65 or older are more than twice as likely to develop melanoma as women in the same age group (The Lifetime risk for Melanoma is 1 in 35 women and 1 in 25 men) and number of cases is about 100,000 per year. According to the International Agency for Research on Cancer, the countries with the highest incidence of cutaneous melanoma are Australia and New Zealand. The incidence of melanoma is increasing, and the therapeutic options for malignant disease are limited, resulting in an increase in the death rate.
The chemotherapy of melanoma is to prevent the metastasis and kill the cancer cells which is including Alkylating Agents (such Dacarbazine (DTIC), response rate is 15% to 20%), Platinum Drugs (such cisplatin, response of 15% as a single treatment) and Microtubule-toxin Agents (such paclitaxel, response rate of 16% as single treatment) and still the side effects are main problem of chemotherapy agents. The current treatment for metastatic melanoma is still poor in overall response and survival rate. Although some bio-chemotherapy trials have shown good outcomes, no agent or regimen has improved median response duration and overall survival in subsequent studies. New treatment options, as single or in combination, with the use of natural phyto-compounds or herbal medicines may provide new agents in the treatment of malignant melanoma.
The natural products are the most consistently successful source of drug leads and provide a greater structural diversity than standard combinatorial chemistry and offer major opportunities for finding novel low molecular weight lead structures that are active against a wide range of assay targets. Traditional Chinese Medicine (TCM) has been practiced for thousands of years with a long history of 2000 to 3000 years and has contributed in the worldwide to the identification of active ingredients for a particular medical usage for several TCM composed of single or multiple herbal components.
In the coming years, the stage is set for a more systematic, rigorous analysis and testing of therapeutic agents used in TCM that may eventually lead to the development of useful therapeutic agents for the entire world. TCM natural products have the potential for use in cancer therapy, for example; artesunate, homoharringtonine, arsenic trioxide and cantharidin, the controlled clinical studies have shown that homoharringtonine and arsenic trioxide can exert profound activity against leukaemia. Increased knowledge of the molecular mechanisms of TCM-derived drugs and recent developments in their applications demonstrate that the combination of TCM with modern cutting-edge technologies provides an attractive strategy for the development of novel and improved cancer therapeutics.
Furthermore, high throughput screening is a new development of strategy to speed up the identification, isolation and characterization process and to discover small natural molecules that can be delivered to use in cancer treatment with less side effects on the human health in the near future. In the present study, we used high throughput screening approaches to investigate the melanoma properties of a compounds fraction library from 500 Chinese herbs and to identify new small natural molecules with anticancer properties against melanoma and other cancer cells.
We have developed a novel HTS-based strategy to systematically identify active natural compounds against any drug target from Chinese medicinal herbs. An herbal compound fraction library was constructed from 500 herbs most frequently used in Traditional Chinese Medicine (TCM) that are likely to contain therapeutic ingredients for a broad spectrum of human diseases including virus infection. For construction of the TCM fraction library, crude herbal extracts were first prepared by 95% ethanol extraction on Soxhlet reflux apparatus followed by automated fractionation of the extracts using preparative HPLC. Eighty fractions were collected from each herb by 0-90% methanol gradient. The number of single compounds in each fraction was ranging from 1 to 17 (averaged 10.4). We have built up a natural compounds library with 40,000 fractions from 500 herbs that is suitable for high throughput screening. Single active compounds from positive fractions are identified by further fractionation, activity analysis and structure determination. For high throughput screening, a working TCM fraction library was prepared in 96-well format by dissolving each fraction in DMSO to make a 20 mM solution suppose average compounds molecular weight is 500 dolton.
A final concentration of 100μM was used to screen for anti-melanoma activity. Among 240 Chinese herbs containing 19,200 fractions screened against human melanoma cancer cell line A375, we identified 154 positive fractions from 67 herbs. We tested the toxicity of positive fractions on freshly isolated mouse splenocytes to exclude fractions toxic to normal cells. The results indicated 110 fractions with remarkable toxicity and 44 fractions with no significant effect on mouse splenocytes. We choose a positive fraction with anti-melanoma activity and least toxicity on splenocytes from a Chinese herb called Artemisia Argyi to isolate positive single compounds that are responsible for the anti-melanoma activity. Organic extraction followed by preparative HPLC fractionation was used to isolate anti-melanoma single compounds from herbal plant Artemisia Argyi. We have successfully isolated two compounds with anti-proliferative effect on A375 melanoma cells. The chemical structures of the two compounds were determined as an O-methylated flavone; Eupatilin (5, 7-dihydroxy-3', 4’, 6-trimethoxyflavone) and jaceosidin (4, 5, 7-trihydroxy-3', 6-dimethoxyflavone) by using MS, 1H NMR and 13C NMR.
The anti-proliferative effect of eupatilin in human melanoma A375 cells was performed by MTT assay. The EC50 value is about 150μM. Eupatilin specifically induced morphological changes in A375 cells and was less toxic to the normal mouse splenocytes. The inhibitory effects of A375 cells were associated with the DNA damage, apoptosis, and cell cycle arrest at G2/M phase in a dose-dependent manner. The apoptotic effects of eupatilin were further verified by using Annexin V-FITC/propidium iodide staining in flow cytometry. It was observed that the apoptosis rates were 13.05% and 29.2% in A375 cells treated with 150 and 300μM eupatilin for 24 h, respectively, compared to the control cells at 2.04%. Furthermore we indicated apoptosis effect by using Hoechst staining (easily detect the fragmentation of DNA in cell nucleus). Flow cytometry was performed to determine whether eupatilin induced cell cycle arrest. The percentage of A375 cells in G2/M phase was increased from 8.82% in untreated cells to 21.70%, and 29.86% in the cells treated for 24h with 150 and 300μM eupatilin, respectively.
These results suggest that our high throughput screening strategy using herbal fraction library is promising in identifying small natural molecules with anti-melanoma activity. The two identified flavones compounds with confirmed anti-melanoma activity perhaps worth further mechanistic and therapeutic studies in human melanoma. Isolation and functional characterization of single compounds from other positive fraction of different herbs may identify new natural compounds with new mechanisms and ideal therapeutic properties against human melanoma.
引文
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