小分子化合物抑制白血病細(xì)胞生長(zhǎng)的分子機(jī)制研究
發(fā)布時(shí)間：2018-07-24 12:17
【摘要】：急性髓細(xì)胞白血病(AML)是一類(lèi)高度異質(zhì)性的惡性血液病,主要特征為源自惡性造血干/組細(xì)胞的髓系白血病細(xì)胞累積。成人白血病患者中有25%的病人是AML患者,并且隨著年齡的增加發(fā)病率增高,故AML患者以老年人居多。盡管約70-80%的AML病人在接受初次化療后能夠獲得完全緩解,但大多數(shù)病人都會(huì)復(fù)發(fā),導(dǎo)致治療失敗而死亡。因此,需要研發(fā)出比傳統(tǒng)化療藥物更為有效、毒副作用更低的藥物,以優(yōu)化AML的治療。本研究主要致力于兩種潛在先導(dǎo)化合物抗白血病活性的分子機(jī)理研究,為開(kāi)發(fā)新的AML治療藥物提供一定的基礎(chǔ)。蟲(chóng)草素是蛹蟲(chóng)草的主要活性成分,結(jié)構(gòu)與腺苷類(lèi)似,具有多種抗腫瘤活性。關(guān)于蟲(chóng)草素的研究很多,然而其抗腫瘤機(jī)制仍有待進(jìn)一步闡明。本研究發(fā)現(xiàn)蟲(chóng)草素能夠通過(guò)誘導(dǎo)細(xì)胞凋亡來(lái)抑制AML細(xì)胞系NB4和U937的生長(zhǎng)。進(jìn)一步的研究表明,蟲(chóng)草素通過(guò)促進(jìn)p53蛋白的累積,增加細(xì)胞色素c的釋放,激活caspase-9,引發(fā)線粒體途徑的細(xì)胞凋亡。蟲(chóng)草素還可以抑制ERK的磷酸化,從而阻斷MAPK信號(hào)通路,使得細(xì)胞對(duì)凋亡信號(hào)更為敏感。同時(shí)我們還發(fā)現(xiàn),蟲(chóng)草素能夠抑制cyclin A2、cyclin E、CDK2的表達(dá),引起細(xì)胞周期的阻滯。深入的研究表明,蟲(chóng)草素誘導(dǎo)DNA損傷,激活Chk2-Cdc25A信號(hào)通路,促進(jìn)Cdc25A的降解,使得CDK2不能被去磷酸化激活,最終造成S期的阻滯。綜上所述,蟲(chóng)草素通過(guò)誘導(dǎo)DNA的損傷引起細(xì)胞周期阻滯和細(xì)胞凋亡,從而抑制NB4和U937細(xì)胞的生長(zhǎng)。海洋萜類(lèi)化合物與陸地萜類(lèi)化合物不同,它們具有許多新的骨架結(jié)構(gòu),并展現(xiàn)出抗腫瘤、抗炎癥、抗菌等多種生物活性。Sesterstatin4/5是一種scalarane型二倍半萜類(lèi)海洋天然產(chǎn)物,具有良好的抗腫瘤活性。在本研究中,我們檢測(cè)了sesterstatin 4/5類(lèi)似物及其中間體的抗白血病活性,發(fā)現(xiàn)包括ZEG-2、ZEG-10、ZEG-11、ZEG-14、ZEG-15在內(nèi)的一組化合物能夠有效抑制HL-60細(xì)胞的生長(zhǎng)。進(jìn)一步的研究發(fā)現(xiàn),ZEG-14和ZEG-15誘導(dǎo)了caspase依賴的細(xì)胞凋亡。并且,它們能夠通過(guò)下調(diào)表達(dá)cyclin A2、cyclin E、CDK2、CDK4,抑制Rb蛋白的磷酸化,引起G0/G1期的阻滯。同時(shí),研究還發(fā)現(xiàn),ZEG-14和ZEG-15誘導(dǎo)了DNA的損傷,激活了ATM/ATR信號(hào)通路,促進(jìn)Cdc25A的降解,使得CDK2和CDK4處于非激活狀態(tài),引起Rb磷酸化受阻,造成細(xì)胞周期的阻滯。綜上所述,ZEG-14和ZEG-15能夠通過(guò)誘導(dǎo)細(xì)胞凋亡和細(xì)胞周期阻滯來(lái)抑制HL-60細(xì)胞的生長(zhǎng)。
[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.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：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.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R733.7
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