小分子化合物抑制白血病细胞生长的分子机制研究
发布时间：2018-07-24 12:17
【摘要】：急性髓细胞白血病(AML)是一类高度异质性的恶性血液病,主要特征为源自恶性造血干/组细胞的髓系白血病细胞累积。成人白血病患者中有25%的病人是AML患者,并且随着年龄的增加发病率增高,故AML患者以老年人居多。尽管约70-80%的AML病人在接受初次化疗后能够获得完全缓解,但大多数病人都会复发,导致治疗失败而死亡。因此,需要研发出比传统化疗药物更为有效、毒副作用更低的药物,以优化AML的治疗。本研究主要致力于两种潜在先导化合物抗白血病活性的分子机理研究,为开发新的AML治疗药物提供一定的基础。虫草素是蛹虫草的主要活性成分,结构与腺苷类似,具有多种抗肿瘤活性。关于虫草素的研究很多,然而其抗肿瘤机制仍有待进一步阐明。本研究发现虫草素能够通过诱导细胞凋亡来抑制AML细胞系NB4和U937的生长。进一步的研究表明,虫草素通过促进p53蛋白的累积,增加细胞色素c的释放,激活caspase-9,引发线粒体途径的细胞凋亡。虫草素还可以抑制ERK的磷酸化,从而阻断MAPK信号通路,使得细胞对凋亡信号更为敏感。同时我们还发现,虫草素能够抑制cyclin A2、cyclin E、CDK2的表达,引起细胞周期的阻滞。深入的研究表明,虫草素诱导DNA损伤,激活Chk2-Cdc25A信号通路,促进Cdc25A的降解,使得CDK2不能被去磷酸化激活,最终造成S期的阻滞。综上所述,虫草素通过诱导DNA的损伤引起细胞周期阻滞和细胞凋亡,从而抑制NB4和U937细胞的生长。海洋萜类化合物与陆地萜类化合物不同,它们具有许多新的骨架结构,并展现出抗肿瘤、抗炎症、抗菌等多种生物活性。Sesterstatin4/5是一种scalarane型二倍半萜类海洋天然产物,具有良好的抗肿瘤活性。在本研究中,我们检测了sesterstatin 4/5类似物及其中间体的抗白血病活性,发现包括ZEG-2、ZEG-10、ZEG-11、ZEG-14、ZEG-15在内的一组化合物能够有效抑制HL-60细胞的生长。进一步的研究发现,ZEG-14和ZEG-15诱导了caspase依赖的细胞凋亡。并且,它们能够通过下调表达cyclin A2、cyclin E、CDK2、CDK4,抑制Rb蛋白的磷酸化,引起G0/G1期的阻滞。同时,研究还发现,ZEG-14和ZEG-15诱导了DNA的损伤,激活了ATM/ATR信号通路,促进Cdc25A的降解,使得CDK2和CDK4处于非激活状态,引起Rb磷酸化受阻,造成细胞周期的阻滞。综上所述,ZEG-14和ZEG-15能够通过诱导细胞凋亡和细胞周期阻滞来抑制HL-60细胞的生长。
[Abstract]:Acute myeloid leukemia (AML) is a highly heterogeneous malignant hematologic disease characterized by the accumulation of myeloid leukemia cells derived from malignant hematopoietic stem / group cells. 25% of adult leukemia patients were AML patients, and the incidence of AML increased with age, so the elderly were the majority of AML patients. Although 70-80% of AML patients can get complete remission after initial chemotherapy, most patients will relapse, leading to failure of treatment and death. Therefore, it is necessary to develop drugs that are more effective and less toxic than traditional chemotherapeutic drugs in order to optimize the treatment of AML. This study focuses on the molecular mechanism of the antileukemia activity of two potential lead compounds and provides a basis for the development of new AML drugs. Cordycepin is the main active component of Cordyceps militaris. There are many studies on Cordycepin, but the mechanism of Cordycepin remains to be further elucidated. It was found that Cordycepin could inhibit the growth of AML cell line NB4 and U937 by inducing apoptosis. Further studies have shown that Cordycepin promotes the accumulation of p53 protein, increases the release of cytochrome c, activates caspase-9, and induces apoptosis in mitochondria pathway. Cordycepin can also inhibit the phosphorylation of ERK, thus blocking the MAPK signaling pathway, making cells more sensitive to apoptotic signals. At the same time, we also found that cordycepin can inhibit the expression of cyclin A _ 2 cyclin EK _ 2 and induce cell cycle arrest. Further studies have shown that Cordycepin induces DNA damage, activates Chk2-Cdc25A signaling pathway, promotes Cdc25A degradation, and makes CDK2 unable to be dephosphorylated, resulting in S phase arrest. In conclusion, Cordycepin inhibits the growth of NB4 and U937 cells by inducing DNA damage, resulting in cell cycle arrest and apoptosis. Marine terpenoids are different from terrestrial terpenoids. They have many new skeleton structures, and exhibit many biological activities, such as anti-tumor, anti-inflammatory, antibacterial and other biological activities. Sesterstatin 4 / 5 is a marine natural product of scalarane type double sesquiterpenoids. It has good anti-tumor activity. In this study, we tested the antileukemic activity of sesterstatin 4 / 5 analogue and its intermediate. We found that a group of compounds including ZEG-2ZEG-10 ZEG-11 ZEG-14 ZEG-15 can effectively inhibit the growth of HL-60 cells. Further studies showed that ZEG-14 and ZEG-15 induced caspase-dependent apoptosis. Moreover, they can inhibit the phosphorylation of RB protein by down-regulating the expression of cyclin A _ 2C _ 2 cyclin, CDK _ 2 and CDK4, and induce the arrest of G0/G1 phase. At the same time, it was also found that ZEG-14 and ZEG-15 induced DNA damage, activated ATM/ATR signaling pathway, promoted Cdc25A degradation, made CDK2 and CDK4 inactive, blocked RB phosphorylation and resulted in cell cycle arrest. In conclusion, ZEG-14 and ZEG-15 can inhibit the growth of HL-60 cells by inducing apoptosis and cell cycle arrest.
【学位授予单位】：上海交通大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R733.7
[Abstract]:Acute myeloid leukemia (AML) is a highly heterogeneous malignant hematologic disease characterized by the accumulation of myeloid leukemia cells derived from malignant hematopoietic stem / group cells. 25% of adult leukemia patients were AML patients, and the incidence of AML increased with age, so the elderly were the majority of AML patients. Although 70-80% of AML patients can get complete remission after initial chemotherapy, most patients will relapse, leading to failure of treatment and death. Therefore, it is necessary to develop drugs that are more effective and less toxic than traditional chemotherapeutic drugs in order to optimize the treatment of AML. This study focuses on the molecular mechanism of the antileukemia activity of two potential lead compounds and provides a basis for the development of new AML drugs. Cordycepin is the main active component of Cordyceps militaris. There are many studies on Cordycepin, but the mechanism of Cordycepin remains to be further elucidated. It was found that Cordycepin could inhibit the growth of AML cell line NB4 and U937 by inducing apoptosis. Further studies have shown that Cordycepin promotes the accumulation of p53 protein, increases the release of cytochrome c, activates caspase-9, and induces apoptosis in mitochondria pathway. Cordycepin can also inhibit the phosphorylation of ERK, thus blocking the MAPK signaling pathway, making cells more sensitive to apoptotic signals. At the same time, we also found that cordycepin can inhibit the expression of cyclin A _ 2 cyclin EK _ 2 and induce cell cycle arrest. Further studies have shown that Cordycepin induces DNA damage, activates Chk2-Cdc25A signaling pathway, promotes Cdc25A degradation, and makes CDK2 unable to be dephosphorylated, resulting in S phase arrest. In conclusion, Cordycepin inhibits the growth of NB4 and U937 cells by inducing DNA damage, resulting in cell cycle arrest and apoptosis. Marine terpenoids are different from terrestrial terpenoids. They have many new skeleton structures, and exhibit many biological activities, such as anti-tumor, anti-inflammatory, antibacterial and other biological activities. Sesterstatin 4 / 5 is a marine natural product of scalarane type double sesquiterpenoids. It has good anti-tumor activity. In this study, we tested the antileukemic activity of sesterstatin 4 / 5 analogue and its intermediate. We found that a group of compounds including ZEG-2ZEG-10 ZEG-11 ZEG-14 ZEG-15 can effectively inhibit the growth of HL-60 cells. Further studies showed that ZEG-14 and ZEG-15 induced caspase-dependent apoptosis. Moreover, they can inhibit the phosphorylation of RB protein by down-regulating the expression of cyclin A _ 2C _ 2 cyclin, CDK _ 2 and CDK4, and induce the arrest of G0/G1 phase. At the same time, it was also found that ZEG-14 and ZEG-15 induced DNA damage, activated ATM/ATR signaling pathway, promoted Cdc25A degradation, made CDK2 and CDK4 inactive, blocked RB phosphorylation and resulted in cell cycle arrest. In conclusion, ZEG-14 and ZEG-15 can inhibit the growth of HL-60 cells by inducing apoptosis and cell cycle arrest.
【学位授予单位】：上海交通大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R733.7
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