非小细胞肺癌天然小分子抑制剂的筛选及其作用机理研究
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摘要
癌症是严重威胁人类健康的重大疾病,仅2008年全球癌症新发病例就达到1270万,死亡例数为760万,随着全球工业化和城镇化的加速发展,癌症的发病率呈日益上升趋势,死于癌症的人数逐年增加,且患者日益年轻化,给社会和家庭带来沉重的经济和精神负担。
在20多种常见癌症中,肺癌已成为危害程度最大的恶性肿瘤之一。无论在发达国家还是发展中国家,肺癌的发病率及死亡率已居各癌症之首。我国目前每年新增肺癌病例已达21万,其死亡率占据了我国城市癌症死亡的第一位。近几年来,肺癌不但发病率呈上升趋势,并且有年轻化倾向。根据临床特征、治疗及预后的不同,肺癌可分为小细胞肺癌(small cell lung cancer, SCLC)和非小细胞肺癌(non-small cell lung cancer, NSCLC)。NSCLC占肺癌病例的80%～85%,是肺癌的主体,虽然恶性程度较低,局部发展慢,但该种肺癌患者体内存在微转移的威胁,给临床的诊断与治疗方案的确定带来巨大困难,据统计在已经确诊的非小细胞肺癌病例中,有超过85%的患者处于中晚期而失去根治性手术治疗的机会。另外非小细胞肺癌对化疗药物的敏感性远较小细胞肺癌差,所以传统的化学药物治疗该类肺癌作用有限。所以因非小细胞肺癌而死亡的病例已是肺癌的主要组成部分,严重危害人类健康。
中晚期的非小细胞肺癌以化学药物治疗为主,目前临床上采用的化疗药物多数疗效有限,具有较大毒副作用,且易被肿瘤耐受,严重影响患者治疗效果。所以,临床上急切需求高效、低副作用、不易被耐受的全新治疗药物。中药是我国传统的天然医药,人们几千年临床探索与用药实践证明中药在治疗疾病,尤其是在治疗重大疑难疾病方面具有独特效果。另外中药还有传统化疗药物不具备的特殊优势：种类繁多,来源广泛；活性化合物具有立体空间结构优势,毒副作用低；作用靶点众多,可以多药联合使用以提高治疗效果；生产和使用成本低。但中药同时也有不可避免的天生劣势：成分复杂,发挥功效的具体成份难以确定；作用靶标不明确,毒副作用不可预见；成药中有效成分含量偏低,质量控制困难,见效缓慢等。这些缺点严重的制约了中药在治疗肿瘤中的应用。所以,分离中药有效成分、明确其作用靶标及作用机理是目前天然药物治疗肿瘤研究中的热点,也是急需解决的难点问题之一。而建立如何从纷繁复杂的天然药物中高效、迅速地分离有效单体成分的方法体系及技术手段则是实现成功分离中药药效成分的关键。
本论文以我国丰富的中药资源为研究对象,着力建立和完善一套高效分离中药有效成分的方法体系及技术手段,并尝试利用该体系高效筛选、分离抗人非小细胞肺癌的新型天然小分子抑制剂。本论文以人肺腺癌细胞系A549为实验对象,采用基于全细胞模型的药物高通量筛选方法顺利地从自行建立的500种中药组分库中发现42味中药对A549有明显的抑制活性,其中包括252个组分,分布于44个组分群(cluster)中。本论文进一步对这些阳性组分的毒副作用进行评估,结果发现对小鼠原代脾细胞毒性较小的中药多达20种,其中包括228个组分。为了筛查现已商品化的单体天然化合物抗非小细胞肺癌的活性,本论文采用同样的高通量筛选方法系统筛查了400种中药活性单体,发现19种单体对A549细胞具有较强的抑制作用(100μM化合物对A549的抑制率均大于50%),土木香内酯为其中之一
本研究进一步对中药柴胡中抑制A549细胞的低毒活性组分进行深入拆分,最终获得单体化合物NSL (A549)-BUP,核磁共振及喷雾质谱对该单体化合物结构分析结果表明NSL (A549)-BUP是分子量为781道尔顿的萜类小分子化合物。对其作用机理进行深入研究,结果表明该化合物诱导细胞凋亡、阻滞A549细胞周期于G2/M期。另外本研究对土木香内酯进行作用机理研究,结果发现该化合物同样能诱导A549细胞凋亡,并阻止其周期于G0/G1及S期。
本研究建立和完善一整套从成分复杂的天然药物中高效分离抑制非小细胞肺癌有效成分的方法体系。以非小细胞肺癌细胞株A549为研究对象,利用高通量筛选技术从500种自行建立的中药组分库及天然小分子单体库中筛选一批非小细胞肺癌的高效抑制剂。为获得高效、低毒的治疗中晚期NSCLC的全新化学结构天然药物奠定基础,也为NSCLC特异分子靶向治疗的天然小分子抑制剂的选择提供依据。本研究中所筛选到的天然小分子抑制剂可能为肺癌发生、发展、转移等机理研究提供全新的化学生物学手段。
Cancer is a serious threat to human health, only in 2008, there were 12.7 million new cases worldwide and about 7.6 million people died from this desease. The incidence of cancer is rising daily with the rapid industrialization and urbanization and the number of people dying from cancer increasing year by year, most of all, there is increasing number of young patients suffering from cancers, which brings to a tremendous financial and emotional burden not only to the society but also to families.
As one of 20 common cancers, lung cancer is becoming one of the most malignant cancers in the world. Lung cancer is on top of the incidence and mortality rate both in developed and developing countries. At present, there are 210 thousand new cases of lung cancer in China each year and the mortality rate is the number one among all cancers in cities of China. The incidence of lung cancer is rising daily and more and more yongers are involved in. According to the clinical pathology characteristics, lung cancer can be divided into two types:small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC is the major one of lung cancer which accounts for 80%-85% lung cancer cases. In spit of the low malignancy and slow development, NSCLC brought a great deal difficulties to the clinical diagnosis and treatment for the threat of micro-metastasis in patients. According to statistics, more than 80% patients with advanced non-small cell lung cancer have lost the chances of receiving surgery treatment. Besides, compared with SCLC, NSCLC is much less sensitive to chemotherapy, consequently, the traditional chemotherapy can benefit little to patients of NSCLC.
Chemotherapy is the standard treatment of advanced non-small cell lung cancer, but the current chemotherapy drugs with greater side effects and easiness to be tolerated benefits little to the NSCLC treatment, which retarded the outcomes of patients greatly. Therefore, new therapeutic drugs with more efficiency but lower side effects are urgently required. Traditional Chinese medicine(TCM) is a natural medicine, whose unique efficiency especially in the treatment of serious deseases was proved by the historical clinical practice in ancient ages. TCM has advantages over the traditional chemotherapy: such as TCM is rich in sources; has superior three-dimensional spatial structure; produces low toxicity; easy to adopt multi-drug combination to improve the therapeutic effect; low-cost in production and application, et al.
However, TCM has unavoidable disadvantages defecting the useness of TCM in the treatment of neoplasms:the active components of TCM are difficult to be isolated; it is difficult to determine the efficacy of specific components; the action targets are not easy to definited; the side effects are unforeseen; there are traces of active components in TCM; the quality control of isolating of active components is difficult; TCM works slowly, et al. Therefore, separation and enrichness of effective components of Chinese medicine, definition of TCM targets, clarification of its mechanism are the intensive interests in the field of cancer treatment research with TCM. How to build techniques and methods system to efficiently separate active components from the complex natural medicines is the key.
In this study, we take efforts to establish and improve an efficient system of methods and technical means for rapid separation of active components from TCM and use this system to screen and isolate new natural small molecules inhibitors of human non-small cell lung cancer. As a result, We sucessfully established an efficient method and technical means system of separation of effective components from TCM. Using this system, we smoothly obtained 42 Chinese herbal medicines with significant inhibitory activity on A549 from the fraction library of 500 Chinese medicine by whole-cell based high-throughput screening method.252 fractions distributed in 44 fractions group (cluster) are involved. The further assays were carried out to assess the toxicity of these positive fractions aganist mouse primary spleen cells. Consequently, up to 20 species of Chinese medicine including 228 components were found low toxic to the primary mouse spleen cells.
Another task of this study was to screen natural single compounds with inhibitory effects on NSCLC.400 natural monomer compounds have been chosen to examine the activity on A549 cell by whole-cell based high-throughput screening and 19 natural single compounds were found to be strong inhibitors of A549 cells, alantolactone was one of them.
This study furtherly divided active fraction of Bupleurum to single compounds, ultimately, the inhibitory single compound NSL (A549)-BUP was obtained. The analysis of molecular structure of NSL (A549)-BUP by NMR and mass spectrometry revealed that this compound was one of Terpenoids with the molecular weight of 781 Dalton. The analysis results of inhibition mechanism showed that NSL (A549)-BUP efficiently induced A549 cell apoptosis, arrested A549 at G2/M phase. Additionally, the apoptosis-inducing effect of alantolactone was found in A549 cell line. Cell cycle arresting assay also clarified that this small molecule compound retarded A549 cycle at the G0/G1 and S phase.
This study successfully established the system for isolation of active single compounds from complex natural medicine for treatment of NSCLC. A number of small molecular natural compounds inhibiting A549 were obtained from fractions library of 500 Chinese medicine and the monomer compound library, which paved the way of obtaining high efficiency yet low toxicity of drugs for the treatment of advanced NSCLC. Meanwhile, the results of this study lay the foundation for choosing specific natural molecular for targeted therapy of NSCLC. The obtained small molecule inhibitors may be used as powerful chemical biology tools to study the mechanisms of the occurrence, development and metastasis of lung cancer.
在20多种常见癌症中,肺癌已成为危害程度最大的恶性肿瘤之一。无论在发达国家还是发展中国家,肺癌的发病率及死亡率已居各癌症之首。我国目前每年新增肺癌病例已达21万,其死亡率占据了我国城市癌症死亡的第一位。近几年来,肺癌不但发病率呈上升趋势,并且有年轻化倾向。根据临床特征、治疗及预后的不同,肺癌可分为小细胞肺癌(small cell lung cancer, SCLC)和非小细胞肺癌(non-small cell lung cancer, NSCLC)。NSCLC占肺癌病例的80%～85%,是肺癌的主体,虽然恶性程度较低,局部发展慢,但该种肺癌患者体内存在微转移的威胁,给临床的诊断与治疗方案的确定带来巨大困难,据统计在已经确诊的非小细胞肺癌病例中,有超过85%的患者处于中晚期而失去根治性手术治疗的机会。另外非小细胞肺癌对化疗药物的敏感性远较小细胞肺癌差,所以传统的化学药物治疗该类肺癌作用有限。所以因非小细胞肺癌而死亡的病例已是肺癌的主要组成部分,严重危害人类健康。
中晚期的非小细胞肺癌以化学药物治疗为主,目前临床上采用的化疗药物多数疗效有限,具有较大毒副作用,且易被肿瘤耐受,严重影响患者治疗效果。所以,临床上急切需求高效、低副作用、不易被耐受的全新治疗药物。中药是我国传统的天然医药,人们几千年临床探索与用药实践证明中药在治疗疾病,尤其是在治疗重大疑难疾病方面具有独特效果。另外中药还有传统化疗药物不具备的特殊优势：种类繁多,来源广泛；活性化合物具有立体空间结构优势,毒副作用低；作用靶点众多,可以多药联合使用以提高治疗效果；生产和使用成本低。但中药同时也有不可避免的天生劣势：成分复杂,发挥功效的具体成份难以确定；作用靶标不明确,毒副作用不可预见；成药中有效成分含量偏低,质量控制困难,见效缓慢等。这些缺点严重的制约了中药在治疗肿瘤中的应用。所以,分离中药有效成分、明确其作用靶标及作用机理是目前天然药物治疗肿瘤研究中的热点,也是急需解决的难点问题之一。而建立如何从纷繁复杂的天然药物中高效、迅速地分离有效单体成分的方法体系及技术手段则是实现成功分离中药药效成分的关键。
本论文以我国丰富的中药资源为研究对象,着力建立和完善一套高效分离中药有效成分的方法体系及技术手段,并尝试利用该体系高效筛选、分离抗人非小细胞肺癌的新型天然小分子抑制剂。本论文以人肺腺癌细胞系A549为实验对象,采用基于全细胞模型的药物高通量筛选方法顺利地从自行建立的500种中药组分库中发现42味中药对A549有明显的抑制活性,其中包括252个组分,分布于44个组分群(cluster)中。本论文进一步对这些阳性组分的毒副作用进行评估,结果发现对小鼠原代脾细胞毒性较小的中药多达20种,其中包括228个组分。为了筛查现已商品化的单体天然化合物抗非小细胞肺癌的活性,本论文采用同样的高通量筛选方法系统筛查了400种中药活性单体,发现19种单体对A549细胞具有较强的抑制作用(100μM化合物对A549的抑制率均大于50%),土木香内酯为其中之一
本研究进一步对中药柴胡中抑制A549细胞的低毒活性组分进行深入拆分,最终获得单体化合物NSL (A549)-BUP,核磁共振及喷雾质谱对该单体化合物结构分析结果表明NSL (A549)-BUP是分子量为781道尔顿的萜类小分子化合物。对其作用机理进行深入研究,结果表明该化合物诱导细胞凋亡、阻滞A549细胞周期于G2/M期。另外本研究对土木香内酯进行作用机理研究,结果发现该化合物同样能诱导A549细胞凋亡,并阻止其周期于G0/G1及S期。
本研究建立和完善一整套从成分复杂的天然药物中高效分离抑制非小细胞肺癌有效成分的方法体系。以非小细胞肺癌细胞株A549为研究对象,利用高通量筛选技术从500种自行建立的中药组分库及天然小分子单体库中筛选一批非小细胞肺癌的高效抑制剂。为获得高效、低毒的治疗中晚期NSCLC的全新化学结构天然药物奠定基础,也为NSCLC特异分子靶向治疗的天然小分子抑制剂的选择提供依据。本研究中所筛选到的天然小分子抑制剂可能为肺癌发生、发展、转移等机理研究提供全新的化学生物学手段。
Cancer is a serious threat to human health, only in 2008, there were 12.7 million new cases worldwide and about 7.6 million people died from this desease. The incidence of cancer is rising daily with the rapid industrialization and urbanization and the number of people dying from cancer increasing year by year, most of all, there is increasing number of young patients suffering from cancers, which brings to a tremendous financial and emotional burden not only to the society but also to families.
As one of 20 common cancers, lung cancer is becoming one of the most malignant cancers in the world. Lung cancer is on top of the incidence and mortality rate both in developed and developing countries. At present, there are 210 thousand new cases of lung cancer in China each year and the mortality rate is the number one among all cancers in cities of China. The incidence of lung cancer is rising daily and more and more yongers are involved in. According to the clinical pathology characteristics, lung cancer can be divided into two types:small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC is the major one of lung cancer which accounts for 80%-85% lung cancer cases. In spit of the low malignancy and slow development, NSCLC brought a great deal difficulties to the clinical diagnosis and treatment for the threat of micro-metastasis in patients. According to statistics, more than 80% patients with advanced non-small cell lung cancer have lost the chances of receiving surgery treatment. Besides, compared with SCLC, NSCLC is much less sensitive to chemotherapy, consequently, the traditional chemotherapy can benefit little to patients of NSCLC.
Chemotherapy is the standard treatment of advanced non-small cell lung cancer, but the current chemotherapy drugs with greater side effects and easiness to be tolerated benefits little to the NSCLC treatment, which retarded the outcomes of patients greatly. Therefore, new therapeutic drugs with more efficiency but lower side effects are urgently required. Traditional Chinese medicine(TCM) is a natural medicine, whose unique efficiency especially in the treatment of serious deseases was proved by the historical clinical practice in ancient ages. TCM has advantages over the traditional chemotherapy: such as TCM is rich in sources; has superior three-dimensional spatial structure; produces low toxicity; easy to adopt multi-drug combination to improve the therapeutic effect; low-cost in production and application, et al.
However, TCM has unavoidable disadvantages defecting the useness of TCM in the treatment of neoplasms:the active components of TCM are difficult to be isolated; it is difficult to determine the efficacy of specific components; the action targets are not easy to definited; the side effects are unforeseen; there are traces of active components in TCM; the quality control of isolating of active components is difficult; TCM works slowly, et al. Therefore, separation and enrichness of effective components of Chinese medicine, definition of TCM targets, clarification of its mechanism are the intensive interests in the field of cancer treatment research with TCM. How to build techniques and methods system to efficiently separate active components from the complex natural medicines is the key.
In this study, we take efforts to establish and improve an efficient system of methods and technical means for rapid separation of active components from TCM and use this system to screen and isolate new natural small molecules inhibitors of human non-small cell lung cancer. As a result, We sucessfully established an efficient method and technical means system of separation of effective components from TCM. Using this system, we smoothly obtained 42 Chinese herbal medicines with significant inhibitory activity on A549 from the fraction library of 500 Chinese medicine by whole-cell based high-throughput screening method.252 fractions distributed in 44 fractions group (cluster) are involved. The further assays were carried out to assess the toxicity of these positive fractions aganist mouse primary spleen cells. Consequently, up to 20 species of Chinese medicine including 228 components were found low toxic to the primary mouse spleen cells.
Another task of this study was to screen natural single compounds with inhibitory effects on NSCLC.400 natural monomer compounds have been chosen to examine the activity on A549 cell by whole-cell based high-throughput screening and 19 natural single compounds were found to be strong inhibitors of A549 cells, alantolactone was one of them.
This study furtherly divided active fraction of Bupleurum to single compounds, ultimately, the inhibitory single compound NSL (A549)-BUP was obtained. The analysis of molecular structure of NSL (A549)-BUP by NMR and mass spectrometry revealed that this compound was one of Terpenoids with the molecular weight of 781 Dalton. The analysis results of inhibition mechanism showed that NSL (A549)-BUP efficiently induced A549 cell apoptosis, arrested A549 at G2/M phase. Additionally, the apoptosis-inducing effect of alantolactone was found in A549 cell line. Cell cycle arresting assay also clarified that this small molecule compound retarded A549 cycle at the G0/G1 and S phase.
This study successfully established the system for isolation of active single compounds from complex natural medicine for treatment of NSCLC. A number of small molecular natural compounds inhibiting A549 were obtained from fractions library of 500 Chinese medicine and the monomer compound library, which paved the way of obtaining high efficiency yet low toxicity of drugs for the treatment of advanced NSCLC. Meanwhile, the results of this study lay the foundation for choosing specific natural molecular for targeted therapy of NSCLC. The obtained small molecule inhibitors may be used as powerful chemical biology tools to study the mechanisms of the occurrence, development and metastasis of lung cancer.
引文
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