基于高通量筛选技术的抗肺腺癌新天然小分子化合物筛选
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摘要
肺癌是世界上最常见的恶性肿瘤之一,其死亡率高居肿瘤死亡之首,近年来其发病率及死亡率均呈明显上升趋势。2002年世界肺癌新发病例1,350,000人,死亡1,180,000人,肺癌占新发恶性肿瘤发病总数的12.4%。在我国的大中城市中,肺癌的死亡率更高居恶性肿瘤首位。2005年我国约有540,000人患肺癌,其中约480,000人死亡。肺癌中腺癌的发病率上升迅速,在美国、加拿大及北欧等国家肺腺癌已超过肺癌总数的一半,在亚裔肺癌患者中,肺腺癌也正将超过鳞癌成为最常见的肺癌类型。尽管手术、放化疗等肺癌传统治疗手段不断发展,但由于70%的肺癌患者在确诊时都属中晚期,往往失去根治性手术机会,而作为肺癌非手术治疗主要手段的化疗,虽然不断改进方案,但是毒副作用大,化疗耐药性等难题仍制约其临床应用及疗效,总体临床疗效令人失望,肺癌的生存期并未得到提高。在美国,其5年生存期不到15%；在发展中国家更低于9%。寻找有效的、毒副作用小的抗癌药物是肺癌治疗的关键。
中草药以其毒副作用较小、药效可靠等优势,成为抗癌新药筛选比较理想的天然产物资源。但由于中药成分复杂、作用机制不明确,大大限制了其在肿瘤治疗方面的开发和利用。高通量筛选是目前药物发现的主流方法,筛选库是其重要的组成部分。与目前常见的组合化合物药物库和药物衍生物药物库相比,天然化合物药库具有数量庞大、结构多样等巨大优势。中药作为筛选样品库更具有应用历史悠久、药效确切等巨大优势。但是,由于化合物分离工作量大,耗时长,目前并没有规模足够大的筛选样品库。因此建立适合高通量筛选的中药样品库,从中发现新的抗癌活性化合物是目前肿瘤药物筛选的新思路。
本研究利用制备型HPLC对500种常见中草药按亲水性排列,连续收集小分子组分建立中药样品组分库。每种草药收集80个组分,建立了含40000个中草药组分的天然小分子样品库。在此样品库基础上,通过细胞增殖抑制测定,针对人肺腺癌A549细胞系进行高通量筛选。以改良MTT法检测细胞活性,在酶标仪540nm波长下测定吸光度A540,计算细胞生长抑制率,抑制率大于50%的药物作为阳性结果。选取脾细胞毒性较小的组分经分析型液相色谱分离纯化后得到活性化合物,结合质谱及核磁技术鉴定化合物结构,确定抗癌活性的单体化合物。在此基础上,进一步检测活性化合物对A549细胞及人外周血白细胞的50%增殖抑制率(IC50)。通过Hoechst33258染色观察活性化合物处理后的细胞形态学变化；通过流式细胞仪分析活性化合物对细胞周期的影响。
本研究结果表明,从500种常见中药成功得到40,000个组分,每个组分所含有的主要成分(可见峰)<20,从而构建成中药高通量筛选组分库。以肺腺癌A549细胞系为药物筛选的细胞模型,在建库的200种中药的16000个组分进行了高通量筛选,其中8种中药共24个组分能够显著抑制肺腺癌细胞A549增殖。这些中药是：远志、益智仁、补骨脂、草薢、藕节、浮小麦、急性子、卷柏。小鼠脾细胞毒性试验发现,急性子及卷柏活性组分处理24小时后的小鼠死亡脾细胞比对照组略有增加,总死亡细胞数目较少,提示其毒副作用较小,因此选择急性子及卷柏进行进一步活性化合物分离。利用分析型HPLC确定了急性子的活性组分E3对应的保留时间13.75分钟,并纯化得到对应的化合物。经过质谱和核磁共振技术分析,急性子的活性单体化合物为槲皮素。槲皮素对A549肺腺癌细胞24小时的50%增殖抑制率(IC50)为10.8μmol/l。这些结果证明了本天然产物高通量筛选体系的可行性及有效性。同样方法,利用分析型HPLC确定了卷柏活性组分G8对应的保留时间为25.80分钟,纯化得到对应的活性化合物,经过质谱和核磁共振技术分析后发现,此化合物为首次从卷柏中分离得到的新的活性单体化合物ALA(考虑今后的新药开发及专利申请,故暂称ALA),其对A549肺癌细胞24小时的IC50为10.2μmol/l。在此基础上,本研究选择首次从卷柏中发现的活性化合物ALA进行进一步药理实验。MTT检测ALA对人的外周血总白细胞毒性的IC50为62.5μmol/l,表明ALA对外周血白细胞毒性作用较小。Hoechst33258染色荧光显微镜下可见ALA处理24小时后的A549细胞内出现明显的高亮蓝色的典型凋亡小体,细胞核呈现染色质凝集,细胞皱缩,细胞核固缩、碎裂、体积变小,荧光强度增高的细胞凋亡特点。通过流式细胞仪分析表明ALA处理的A549细胞周期受到调控,G2/M期细胞相对增多,肿瘤细胞出现凋亡。另外,对其他阳性中药组分的活性单体化合物分离和作用机制的研究工作正在进行中。
综上所述,本研究1.成功建立了适用于高通量筛选的中药样品组分库；2.从中药组分库中筛选出抑制人肺腺癌A549细胞增殖的8种中药的24个组分；3.成功从中药急性子中分离得到活性单体化合物槲皮素,证明了目前的HTS系统的可行性及有效性；4.首次从中药卷柏中分离出活性单体化合物ALA；5.ALA可阻滞A549细胞于G2/M期,从而使肿瘤细胞增殖减缓；6.ALA可诱导肺腺癌A549细胞凋亡；7.ALA具有毒性小,抑癌活性强的特点,为肺腺癌的治疗提供了新的途径；8.其他6种阳性中药组分的活性单体化合物分离及机制的研究工作正在进行中。
Lung cancer is one of the most cancers and the leading cause of cancer death in the world. Recently, its incidence and mortality showed a clear upward trend. In 2002, there were 1,350,000 new cases of lung cancer in the world, and 1,180,000 people were dead. In China, lung cancer has the highest mortality rate among all the cancers in the city dwellers. In 2005, there were 540,000 new cases of lung cancer in China, and 480,000 people were dead. The major patients of lung cancer are non-small cell lung cancer (NSCLC), which comprises approximately 80% of lung cancer patients. In recent years, the incidence of lung adenocarcinoma, a subtype of NSCLC, is increasing and becoming the most subtype of lung cancer in Asian patients. Such as surgery, radiotherapy and chemotherapy, the conventional treatment of lung cancer have provided some new avenues for therapeutic strategies. However, certain patients are still plagued by rapid disease recurrence and progression. Particularly, lung adenocarcinoma is often at the stages beyond surgical remedy and resistant to chemotherapy and radiation. There has been no significant improvement in the overall survival. The 5-year survival rate of lung cancer is less than 15% in U.S.A and 9% in developing countries. The chemotherapeutic benefits and the prognosis of lung adenocarcinoma remain to be promoted. Thus, the development of new anti-lung adenocarcinoma drugs becomes more important and urgent issue.
Traditional Chinese medicine (TCM) is a kind of natural products, and generally low in cost, rich in resource. In clinical practice, TCM has been prescribed for many diseases over centuries and show very little toxicity or side effects. Recently, TCM began to be matched by increasing scientific attention as an important resource of screening new drug worldwide. However, despite the vast interest and increasing demand, the complexity of TCM and the lack of credible data for its mechanism are the main obstacles toward the treatment for many diseases, such as cancer. High throughput screening (HTS) is the major technique of drug discovery. Drug library is the important part of HTS. Compared with combinatorial chemistry compound and derivatives of proved drugs, the natural compound library shows many great advantages such as plentiful and structural diversity. However, there is no such an ideal herbal-based natural compound library that has good therapeutic coverage and is suitable for HTS. It is necessary to create such sample database of TCM and find anti-cancer drugs from it.
Our strategy is to build up a TCM compound fraction library from a collection of most frequently used 500 TCM according hydrophilic. The library consisted of 40,000 fractions from Chinese traditional medicines. For construction of this library, HPLC was used for the separation of the TCM fractions. We select lung adenocarcinoma A549 cell line as the model to screen the potential anti-tumor small molecules. We performed our HTS with modified MTT assay, and the absorbance at 540nm (A540) was read on a spectrophotometric plate reader. The proportion of surviving cells and he inhibition rate were calculated. The IC50 values were obtained according the inhibition rate. The fractions whose inhibition rate was above 50% was defined as the positive. Preparative and analytical HPLC were used for the separation and purification of active compounds. Mass spectrometer (MS) and nuclear magnetic resonance (NMR) techniques were selected to determine the chemical structure of anti-cancer active compound. The toxicity of active compound was detected by MTT method on A549 cells and human peripheral blood leukocytes. Hoechst33258 staining was used to find out the morphological changes after drug treatment. The effect of active compound on the cell cycle was analyzed by flow cytometry.
The results indicated the TCM compound fraction library including 40,000 fractions was successfully built up, in which each fraction contained less than 20 main components. On the basis of this library, we screened 16,000 fractions from 200 TCM and found 24 fractions of 8 TCM with the ability of inhibiting to the growth of A549 cells. These herbs are:Thinleaf Milkwort Root, Sharpleaf Galangal Fruit, Malaytea Scurfpea Fruit. Sevenlobed Yam Rhizome, Lotus Rhizome Node, Blighted Wheat, Garden Balsam Seed and Selaginella tamariscina. The toxicity test of these drug fractions on the mouse spleen cells showed that Garden Balsam Seed and Selaginella tamariscina are less toxic to spleen cells. So far, Garden Balsam Seed and Selaginella tamariscina were chose for the separation of the active compound. The analytical HPLC showed that the retention time of the active fraction E3 in Garden Balsam Seed is 13.75min. MS and NMR technology identified that the active compound is quercetin. The IC50 value of quercetin against A549 cells is 10.8umol/l. By the same method, the analytical HPLC showed that the retention time of the active fraction G8 in Selaginella tamariscina is 25.80min. MS and NMR technology identified that the active compound is ALA. The IC50 value of ALA against A549 cells is 10.2umol/l. Many articles have described the anti-cancer mechanism of quercetin, but less about ALA. So far, we further studied the anti-cancer mechanism of ALA by morphological observation and flow cytometry. We found that the IC50 value of ALA against human peripheral blood leukocytes is 62.5umol/l. This result indicated ALA has little toxic effect on peripheral blood leukocytes. By Hoechst staining, we found apparent apoptosis bodies in treatment group. At the same time, flow cytometry showed that the cell cycle of A549 treated by ALA is blocked in G2/M phase. These results suggested that ALA can induce apoptosis for A549 cell. In addition, the separation and identification of other 6 active compounds were in progress.
Taken together, the present study demonstrates that 1. The TCM compound fraction library for HTS was successfully built up.2.24 active anti-cancer ingredients of 8 TCM were found from our library; 3. The successful separation of quercetin from Garden Balsam Seed proved that our HTS system is feasible and credible:4. The anti-cancer active compound ALA was separated from Selaginella tamariscina for the first time; 5. ALA can inhibit A549 cells course at G2/M phase, then slow down cells proliferation.6. ALA can induce the apoptosis of A549 cells; 7. Because ALA has the traits of low toxicity and strong inhibition, it will provide a new therapy for the lung adenocarcinoma; 8. The separation of other 6 active compounds is in progress.
中草药以其毒副作用较小、药效可靠等优势,成为抗癌新药筛选比较理想的天然产物资源。但由于中药成分复杂、作用机制不明确,大大限制了其在肿瘤治疗方面的开发和利用。高通量筛选是目前药物发现的主流方法,筛选库是其重要的组成部分。与目前常见的组合化合物药物库和药物衍生物药物库相比,天然化合物药库具有数量庞大、结构多样等巨大优势。中药作为筛选样品库更具有应用历史悠久、药效确切等巨大优势。但是,由于化合物分离工作量大,耗时长,目前并没有规模足够大的筛选样品库。因此建立适合高通量筛选的中药样品库,从中发现新的抗癌活性化合物是目前肿瘤药物筛选的新思路。
本研究利用制备型HPLC对500种常见中草药按亲水性排列,连续收集小分子组分建立中药样品组分库。每种草药收集80个组分,建立了含40000个中草药组分的天然小分子样品库。在此样品库基础上,通过细胞增殖抑制测定,针对人肺腺癌A549细胞系进行高通量筛选。以改良MTT法检测细胞活性,在酶标仪540nm波长下测定吸光度A540,计算细胞生长抑制率,抑制率大于50%的药物作为阳性结果。选取脾细胞毒性较小的组分经分析型液相色谱分离纯化后得到活性化合物,结合质谱及核磁技术鉴定化合物结构,确定抗癌活性的单体化合物。在此基础上,进一步检测活性化合物对A549细胞及人外周血白细胞的50%增殖抑制率(IC50)。通过Hoechst33258染色观察活性化合物处理后的细胞形态学变化；通过流式细胞仪分析活性化合物对细胞周期的影响。
本研究结果表明,从500种常见中药成功得到40,000个组分,每个组分所含有的主要成分(可见峰)<20,从而构建成中药高通量筛选组分库。以肺腺癌A549细胞系为药物筛选的细胞模型,在建库的200种中药的16000个组分进行了高通量筛选,其中8种中药共24个组分能够显著抑制肺腺癌细胞A549增殖。这些中药是：远志、益智仁、补骨脂、草薢、藕节、浮小麦、急性子、卷柏。小鼠脾细胞毒性试验发现,急性子及卷柏活性组分处理24小时后的小鼠死亡脾细胞比对照组略有增加,总死亡细胞数目较少,提示其毒副作用较小,因此选择急性子及卷柏进行进一步活性化合物分离。利用分析型HPLC确定了急性子的活性组分E3对应的保留时间13.75分钟,并纯化得到对应的化合物。经过质谱和核磁共振技术分析,急性子的活性单体化合物为槲皮素。槲皮素对A549肺腺癌细胞24小时的50%增殖抑制率(IC50)为10.8μmol/l。这些结果证明了本天然产物高通量筛选体系的可行性及有效性。同样方法,利用分析型HPLC确定了卷柏活性组分G8对应的保留时间为25.80分钟,纯化得到对应的活性化合物,经过质谱和核磁共振技术分析后发现,此化合物为首次从卷柏中分离得到的新的活性单体化合物ALA(考虑今后的新药开发及专利申请,故暂称ALA),其对A549肺癌细胞24小时的IC50为10.2μmol/l。在此基础上,本研究选择首次从卷柏中发现的活性化合物ALA进行进一步药理实验。MTT检测ALA对人的外周血总白细胞毒性的IC50为62.5μmol/l,表明ALA对外周血白细胞毒性作用较小。Hoechst33258染色荧光显微镜下可见ALA处理24小时后的A549细胞内出现明显的高亮蓝色的典型凋亡小体,细胞核呈现染色质凝集,细胞皱缩,细胞核固缩、碎裂、体积变小,荧光强度增高的细胞凋亡特点。通过流式细胞仪分析表明ALA处理的A549细胞周期受到调控,G2/M期细胞相对增多,肿瘤细胞出现凋亡。另外,对其他阳性中药组分的活性单体化合物分离和作用机制的研究工作正在进行中。
综上所述,本研究1.成功建立了适用于高通量筛选的中药样品组分库；2.从中药组分库中筛选出抑制人肺腺癌A549细胞增殖的8种中药的24个组分；3.成功从中药急性子中分离得到活性单体化合物槲皮素,证明了目前的HTS系统的可行性及有效性；4.首次从中药卷柏中分离出活性单体化合物ALA；5.ALA可阻滞A549细胞于G2/M期,从而使肿瘤细胞增殖减缓；6.ALA可诱导肺腺癌A549细胞凋亡；7.ALA具有毒性小,抑癌活性强的特点,为肺腺癌的治疗提供了新的途径；8.其他6种阳性中药组分的活性单体化合物分离及机制的研究工作正在进行中。
Lung cancer is one of the most cancers and the leading cause of cancer death in the world. Recently, its incidence and mortality showed a clear upward trend. In 2002, there were 1,350,000 new cases of lung cancer in the world, and 1,180,000 people were dead. In China, lung cancer has the highest mortality rate among all the cancers in the city dwellers. In 2005, there were 540,000 new cases of lung cancer in China, and 480,000 people were dead. The major patients of lung cancer are non-small cell lung cancer (NSCLC), which comprises approximately 80% of lung cancer patients. In recent years, the incidence of lung adenocarcinoma, a subtype of NSCLC, is increasing and becoming the most subtype of lung cancer in Asian patients. Such as surgery, radiotherapy and chemotherapy, the conventional treatment of lung cancer have provided some new avenues for therapeutic strategies. However, certain patients are still plagued by rapid disease recurrence and progression. Particularly, lung adenocarcinoma is often at the stages beyond surgical remedy and resistant to chemotherapy and radiation. There has been no significant improvement in the overall survival. The 5-year survival rate of lung cancer is less than 15% in U.S.A and 9% in developing countries. The chemotherapeutic benefits and the prognosis of lung adenocarcinoma remain to be promoted. Thus, the development of new anti-lung adenocarcinoma drugs becomes more important and urgent issue.
Traditional Chinese medicine (TCM) is a kind of natural products, and generally low in cost, rich in resource. In clinical practice, TCM has been prescribed for many diseases over centuries and show very little toxicity or side effects. Recently, TCM began to be matched by increasing scientific attention as an important resource of screening new drug worldwide. However, despite the vast interest and increasing demand, the complexity of TCM and the lack of credible data for its mechanism are the main obstacles toward the treatment for many diseases, such as cancer. High throughput screening (HTS) is the major technique of drug discovery. Drug library is the important part of HTS. Compared with combinatorial chemistry compound and derivatives of proved drugs, the natural compound library shows many great advantages such as plentiful and structural diversity. However, there is no such an ideal herbal-based natural compound library that has good therapeutic coverage and is suitable for HTS. It is necessary to create such sample database of TCM and find anti-cancer drugs from it.
Our strategy is to build up a TCM compound fraction library from a collection of most frequently used 500 TCM according hydrophilic. The library consisted of 40,000 fractions from Chinese traditional medicines. For construction of this library, HPLC was used for the separation of the TCM fractions. We select lung adenocarcinoma A549 cell line as the model to screen the potential anti-tumor small molecules. We performed our HTS with modified MTT assay, and the absorbance at 540nm (A540) was read on a spectrophotometric plate reader. The proportion of surviving cells and he inhibition rate were calculated. The IC50 values were obtained according the inhibition rate. The fractions whose inhibition rate was above 50% was defined as the positive. Preparative and analytical HPLC were used for the separation and purification of active compounds. Mass spectrometer (MS) and nuclear magnetic resonance (NMR) techniques were selected to determine the chemical structure of anti-cancer active compound. The toxicity of active compound was detected by MTT method on A549 cells and human peripheral blood leukocytes. Hoechst33258 staining was used to find out the morphological changes after drug treatment. The effect of active compound on the cell cycle was analyzed by flow cytometry.
The results indicated the TCM compound fraction library including 40,000 fractions was successfully built up, in which each fraction contained less than 20 main components. On the basis of this library, we screened 16,000 fractions from 200 TCM and found 24 fractions of 8 TCM with the ability of inhibiting to the growth of A549 cells. These herbs are:Thinleaf Milkwort Root, Sharpleaf Galangal Fruit, Malaytea Scurfpea Fruit. Sevenlobed Yam Rhizome, Lotus Rhizome Node, Blighted Wheat, Garden Balsam Seed and Selaginella tamariscina. The toxicity test of these drug fractions on the mouse spleen cells showed that Garden Balsam Seed and Selaginella tamariscina are less toxic to spleen cells. So far, Garden Balsam Seed and Selaginella tamariscina were chose for the separation of the active compound. The analytical HPLC showed that the retention time of the active fraction E3 in Garden Balsam Seed is 13.75min. MS and NMR technology identified that the active compound is quercetin. The IC50 value of quercetin against A549 cells is 10.8umol/l. By the same method, the analytical HPLC showed that the retention time of the active fraction G8 in Selaginella tamariscina is 25.80min. MS and NMR technology identified that the active compound is ALA. The IC50 value of ALA against A549 cells is 10.2umol/l. Many articles have described the anti-cancer mechanism of quercetin, but less about ALA. So far, we further studied the anti-cancer mechanism of ALA by morphological observation and flow cytometry. We found that the IC50 value of ALA against human peripheral blood leukocytes is 62.5umol/l. This result indicated ALA has little toxic effect on peripheral blood leukocytes. By Hoechst staining, we found apparent apoptosis bodies in treatment group. At the same time, flow cytometry showed that the cell cycle of A549 treated by ALA is blocked in G2/M phase. These results suggested that ALA can induce apoptosis for A549 cell. In addition, the separation and identification of other 6 active compounds were in progress.
Taken together, the present study demonstrates that 1. The TCM compound fraction library for HTS was successfully built up.2.24 active anti-cancer ingredients of 8 TCM were found from our library; 3. The successful separation of quercetin from Garden Balsam Seed proved that our HTS system is feasible and credible:4. The anti-cancer active compound ALA was separated from Selaginella tamariscina for the first time; 5. ALA can inhibit A549 cells course at G2/M phase, then slow down cells proliferation.6. ALA can induce the apoptosis of A549 cells; 7. Because ALA has the traits of low toxicity and strong inhibition, it will provide a new therapy for the lung adenocarcinoma; 8. The separation of other 6 active compounds is in progress.
引文
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