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Effects of compound YSY-01A, a novel proteasome inhibitor, on MGC-803 cells and its related mechanism

Journal of Chinese Pharmaceutical Sciences 2014年第9期23卷 601-609页

作者：陈溢欣袁霞葛泽梅冉福香吴军李润涛崔景荣北京大学医学部天然药物及仿生药物国家重点实验室北京100191 北京大学医学部药学院化学生物学系北京100191

As a novel proteasome inhibitor, remarkable proliferation inhibitory effect of compound YSY-01A was shown on tumor cells in previous studies. However, few studies has reported its effect on gastric cancer and related mechanism. We evaluated the anti-proliferative effect of compound YSY-01A using MGC-803 cells and its anti-tumor effect using xenograft nu-BALB/c mouse model. Cell proliferation inhibition was assessed by SRB assay. Related protein expression levels were determined by Western blot assay. We observed that the compound YSY-01A had a significant proliferation inhibitory effect on MGC-803 cells in vitro. Experiment in vivo showed that the compound YSY-01A had a remarkable growth inhibitory effect on MGC-803 cells xenograft tumor when it was used either alone or in combination with the conventional chemotherapeutic agent 5-fluorouracil （5-FU）. Furthermore, YSY-01A and 5-FU had a synergistic effect on xenograft tumor. Results of molecular experiment showed that the compound YSY-01A had a remarkable inhibitory effect on TNF-c~ and IFN induced NF-KB nuclear translocation. At the same time, the compound YSY-01A could reduce the expression of IKK-~, IL-I~ and iNOS, while it significantly enhanced the expression of COX-2 in MGC-803 ceils. Taken together, compound YSY-01A had an impressive tumor inhibitory effect, and it worked in NF-KB-related pathway, suggesting that the compound YSY-01A was an effective therapeutic drug for patients with gastric cancer. Higher tumor cell growth inhibition after the treatment in a combination with 5-FU indicated that combining YSY-01A with 5-FU might be more effective for displaying tumor cell growth inhibitory effects on gastric cancer cells.

关键词： Proteasome inhibitor YSY-01A MGC-803 cell line NF-kB Anti-tumor

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Effects of compound 209 on colorectal cancer cell HT-29 in vivo and in vitro

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Journal of Chinese Pharmaceutical Sciences 2013年第1期22卷 89-94页

作者：蒋晓袁霞楚明明郭维刘敬弢冉福香葛泽梅李润涛崔景荣北京大学医学部天然药物及仿生药物国家重点实验室北京100191 北京大学医学部药学院化学生物学系北京100191

Compound 209 is a newly synthesized dithiocarbamate derivative with antiproliferation activity in vitro, however, its antitumor effect in vivo and the underlying mechanisms have yet to be identified. We explored the antitumor effect of compound 209 and the possible mechanisms for its inhibition of the growth of HT-29 xenograff tumor and proliferation of HT-29 cells. Cell proliferation was evaluated with SRB assay in vitro. The results showed that compound 209 had significant antiproliferation activity on HT-29 cells. Furthermore, the xenograff HT-29 nude mouse model was used to study the antitumor effect of compound 209 in vivo. We found that compound 209 significantly inhibited tumor growth and did not cause loss of body weight or leukocytopenia. Analysis by flow cytometry indicated that compound 209 arrested HT-29 cell cycle in G~ phase. Western blotting analysis suggested that compound 209 increased the expression of p27, cyclin E, CDK2, cyclin D1 and CDK4. These results demonstrated the antitumor effect of compound 209 and its potential use as an anticancer drug.

关键词： Dithiocarbamate Compound 209 Cell cycle Cell cycle-related proteins HT-29 cell line

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Effects and mechanism of proteasome inhibitor YSY01--A alone or in combination with cisplatin against A549 cells in vitro

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Journal of Chinese Pharmaceutical Sciences 2015年第9期24卷 607-616页

作者：孙婷袁霞黄薇郭维葛泽梅李润涛崔景荣北京大学医学部天然药物及仿生药物国家重点实验室北京100191 北京大学医学部药学院化学生物学系北京100191

YSY01-A, as a novel proteasome inhibitor, has shown remarkable proliferation inhibitory effect on certain types of tumor cells. However, few studies have reported its effect on non-small cell lung cancer （NSCLC）, and its underlying mechanism remains unknown. In our present study, we aimed to figure out the inhibitory effects as well as the mechanism of proteasome inhibitor YSY01-A against A549 cells both individually and in combination with cisplatin. A549 cell proliferation inhibition was assessed by SRB assay. Its related protein expression levels were determined by western blot assay. Moreover, the change of intracellular cisplatin accumulation was examined by ICP-MS assay. The results suggested that YSY01-A significantly （P〈0.001） inhibited the proliferation of A549 cells （IC50 was 36.2 nM for 72 h） in a concentration-dependent and time-dependent manner. Compared with the negative control group, YSY01-A （60 nM, 48 h） down-regulated PI3K/Akt pathway in A549 cells by increasing the expression level of PTEN （P〈0.01）, and decreasing the expression level of PI3K （P〈0.001） and p-Akt/Akt （P〈0.001）. When combined with cisplatin, YSY01-A of different concentrations （5, 10, 20 nM） could significantly increase the inhibition effects on A549 cells compared with the cisplatin alone treatment, showing a synergistic effect. At the same time, YSY01-A could remarkably block the cisplatin-induced down-regulation of hCTR1 in a concentration-dependent manner and increase cisplatin uptake from 2.01 to 2.47 fold （P〈0.001）. In conclusion, compound YSY01-A could significantly inhibit proliferation of NSCLC A549 cells, showing a strong synergistic effect when combined with cisplatin. Down-regulation of PI3K/Akt pathway might be the mechanism of inhibitory effect of YSY0 l-A, and the combination with cisplatin might increase the expression of CTR1 and intracellular cisplatin accumulation.

关键词： Proteasome inhibitor A549 Cisplatin combination PTEN CTR1 Antitumor

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DNA damaging effect of SLXM-2, a derivative of cyclophosphamide, on hepatocarcinoma H_(22) cells in vivo

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Journal of Chinese Pharmaceutical Sciences 2014年第1期23卷 16-21页

作者：楚明明袁霞贾璇孙婷郭维蒋晓刘敬弢李润涛崔景荣北京大学医学部天然药物及仿生药物国家重点实验室北京100191 北京大学医学部药学院化学生物学系北京100191

Compound SLXM-2, a derivative of cyclophosphamide （CTX）, has shown potent growth-inhibitory effect on tumor cells with low toxicity in previous studies. However, the mechanism of its anti-tumor effect, especially on DNA damage, remains largely unclear. This study investigated the effect of SLXM-2 on the survival time of mice transplanted with the ascitie fluid-type hepatocarcinoma 22 （H22）. We also evaluated the correlation between DNA damaging effect of SLXM-2 and its anti-tumor effect, and to probe the possible molecular mechanism for its effect on H22 cells. The results suggested that SLXM-2 significantly （P〈0.05） prolonged the survival time of mice bearing the ascitic fluid-type H22. Furthermore, SLXM-2 induced DNA damage in a dose-dependent manner in H22 cells. Further investigation revealed that SLXM-2 significantly （P〈0.05） up-regulated the expression levels of a series of DNA damage-related proteins, such as γH2AX （Ser139）, p-Chkl （Ser296）, p-Chk2 （Thr68）, p-p53 （Ser15）, p-p53 （Ser20） and p21, and down-regulated the expression of p-ATR （Ser428） and p-ATM （Ser1981）. In conclusion, SLXM-2 showed a remarkable anti-tumor activity on ascitic fluid-type H22 cells, and its molecular mechanism is related to its DNA damaging effect.

关键词： SLXM-2 H22 DNA damage SCGE DNA damage-related proteins

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Cell cycle arrest effect of compound YSY-01A, a new proteasome inhibitor,on SK-OV-3 cells

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Journal of Chinese Pharmaceutical Sciences 2013年第6期22卷 483-490页

作者：贾璇袁霞楚明明冉福香李润涛崔景荣北京大学医学部天然药物及仿生药物国家重点实验室北京100191 北京大学医学部药学院化学生物学系北京100191

Compound YSY-01A, a recently synthesized proteasome inhibitor, has shown potent growth-inhibitory effect on tumor cells in previous researches. However, the mechanism of its inhibitory effects, especially on cell cycle, remains largely unclear. This study aimed to evaluate the correlation between cell cycle arrest effect of YSY-01A and its anti-cancer effect, and to probe the possible molecular mechanisms for its effects on human ovarian cancer SK-OV-3 cells. The results suggested that YSY-01A significantly （P〈0.05） inhibited cellular proliferation of SK-OV-3 cells in a concentration-dependent and time-dependent manner. Furthermore, YSY-01A induced a G2/M cell cycle arrest of SK-OV-3 cells. Further investigation revealed that YSY-01A significantly （P〈0.05） changed the expression levels of a series of cell cycle related protein, such as cyclin B1, cdc2, and p-cdc2 （T14）. Meanwhile, YSY-01A could inhibit the TNF-a-induced NF-kB nuclear translocation and lead to the increase of 1kBa as well as the decrease of IKK and Gadd45a In conclusion, YSY-01A showed remarkable anti-cancer activity on SK-OV-3 cells, and its molecular mechanisms were related to G2/M cell cycle arrest.

关键词： Proteasome inhibitor YSY-01A SK-OV-3 Cell-cycle related protein High content screening

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Reactive oxygen species mediate ethaselen-induced rapid apoptosis in A549 cells

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Journal of Chinese Pharmaceutical Sciences 2014年第1期23卷 54-59页

作者：熊堃徐伟曾慧慧北京大学医学部天然药物及仿生药物国家重点实验室北京100191 北京大学医学部药学院化学生物学系北京100191

Thioredoxin reductase （TrxR） is an important enzyme responsible for the removal of excess reactive oxygen species （ROS） in mammalian cells. This study aimed to investigate the roles of ROS in the anti-tumor effects of ethaselen, a TrxR inhibitor. In a human lung cancer cell line A549, we observed rapidly elevated ROS levels, loss of mitochondrial potential, and cell death with the treatment of ethaselen. Such changes were prevented when cells were pre-incubated with of N-acetyl-cysteine （NAC）, a ROS scavenger. The apoptosis study by Annexin V-PI assay and protein assay by Western blot suggested that mitochondrial pathway was involved in the initiation of apoptosis. In ethaselen-treated cells, cyclosporin A （CsA）, an inhibitor of mitochondrial permeability transition pores （PTPs）, inhibited the release of cytochrome c and reduced cell death in ethaselen-treated cells, while the protein levels of some Bcl-2 family proteins remained unchanged. These results suggest that ROS mediated the ethaselen-induced rapid apoptosis, at least, partially through the enhancement of mitochondrial membrane permeability, which may ultimately lead to the release of pro-apoptotic proteins. Our study, for the first time, demonstrated that the anti-tumor effects of ethaselen, including the early phase of cellular response, are associated with ROS. More studies are needed to confirm our conclusion, as well as to further explore the underlying mechanisms in the anti-tumor effects of ethaselen.

关键词： Ethaselen Reactive oxygen species Anti-cancer Apoptosis Mitochondria

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阿尔茨海默症病理机制中的金属代谢和金属药物

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中国科学：化学 2014年第4期44卷 541-554页

作者：张悦夏青杨晓达王夔天然和仿生药物国家重点实验室北京大学医学部药学院化学生物学系北京100191

随着人口老龄化进程的发展,阿尔茨海默症(AD)已成为威胁中国和世界人口健康和经济的重大疾病.本文综述了近年来AD病理的分子机制的新进展,分析了其中金属代谢的意义.研究发现,在AD进程中,围绕淀粉样斑块(AP)和神经缠绕斑(NFT)的形成,多... 详细信息

随着人口老龄化进程的发展,阿尔茨海默症(AD)已成为威胁中国和世界人口健康和经济的重大疾病.本文综述了近年来AD病理的分子机制的新进展,分析了其中金属代谢的意义.研究发现,在AD进程中,围绕淀粉样斑块(AP)和神经缠绕斑(NFT)的形成,多因素相互联系并发挥作用,这些主要因素包括金属内稳态、胰岛素抵抗、神经炎症、线粒体和血脑屏障改变等.与AD病理过程密切相关的主要蛋白质均参与了金属元素的生理代谢过程,而细胞金属离子的内稳态失衡加剧了AD病理的恶化.金属药物在AD诊断和治疗中可能具有以下的发展潜力:(1)AD早期诊断探针;(2)调节金属内稳态的配体和/或微量元素补充;(3)抗糖尿病金属配合物;(4)神经元和血脑屏障(BBB)保护金属药物.

关键词：阿尔茨海默症金属药物金属内稳态配体疗法神经保护

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大鼠血浆中新型α7-烟碱型乙酰胆碱受体正向变构调节剂LD486的液相色谱-质谱串联测定方法学的建立及其药代动力学特征（英文）

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Journal of Chinese Pharmaceutical Sciences 2016年第7期25卷 517-525页

作者：黄晓敏焦文宣孙崎王克威北京大学医学部药学院分子与细胞药理学系北京大学医学部天然药物及仿生药物国家重点实验室北京大学医学部药学院化学生物学系

神经型α7-烟碱型乙酰胆碱受体功能的不足与认知缺陷以及多种神经精神障碍相关。在动物模型中,激活α7-烟碱型乙酰胆碱受体可以提高学习记忆能力以及感觉门控。为了增强新型的功能,我们通过筛选发现了激动α7-烟碱型乙酰胆碱受体的正向... 详细信息

神经型α7-烟碱型乙酰胆碱受体功能的不足与认知缺陷以及多种神经精神障碍相关。在动物模型中,激活α7-烟碱型乙酰胆碱受体可以提高学习记忆能力以及感觉门控。为了增强新型的功能,我们通过筛选发现了激动α7-烟碱型乙酰胆碱受体的正向调节剂LD486。在本研究中,我们建立了一个简单可靠且高效的液相色谱质谱联用的方法（LC-MS/MS）并分析了这种新型的正向变构调节剂LD486在大鼠血浆中的浓度以及药代动力学参数。含有LD486的血浆样品用反向C18色谱柱分离,流动相为乙腈和0.1%甲酸水溶液（80:20,v/v）,流速为0.5 mL/min,内标为A1223。液相流出液使用电喷雾离子源（ESI,正离子模式）,质谱多反应监测模式检测,检测离子:LD486为m/z 419.0[M+H];→m/z 169.0,A1223为m/z 400.0[M+H]+→m/z 129.9。LD486在4–4000 ng/m L范围内,线性关系良好,最低定量限为4 ng/m L。在最低定量限时,依然有满意的日内日间精密度,提取回收率,以及基质效应。稳定性测试提示血浆中LD486在反复冻融,22oC室温下放置2小时和12小时,以及–20oC保存2周均保持稳定。我们将此方法成功地应用到测定大鼠血浆中LD486静脉注射（1 mg/kg）以及口服（3 mg/kg和30 mg/kg）后给药途径的药代动力学特征。

关键词：乙酰胆碱受体正向变构调节剂 LD486 液相色谱质谱联用药代动力学大鼠血浆 α7受体通道

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Theβ-directing effect of ionic liquid in mannopyranosylation:a potential access to stereoselective construction of the 1,2-cis-β-D-mannopyranosyl linkage

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Journal of Chinese Pharmaceutical Sciences 2011年第6期20卷 549-556页

作者：孙晟马庆孟祥豹李庆李树春黄河清李中军北京大学医学部天然药物及仿生药物国家重点实验室药学院化学生物学系北京100191

We report a novel P-directing effect of imidazolium based ionic liquid,which was observed when we conducted the glycosylation of a 6-O-acetyl-2,3,4-tri-O-benzyl-mannose trichloroacetimidate donor with a modified ionic liquid support acceptor. The mechanism was investigated and a hypothesis was *** optimization of the reaction conditions,an innovative method for the selective construction of 1,2-cis-β-D-mannopyranosyl linkage was developed.

关键词： Ionic liquid supported strategy Glycosylation Stereoselectivity

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Vanadium stimulates mitochondrial ROS production in different ways

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Journal of Chinese Pharmaceutical Sciences 2011年第5期20卷 498-504页

作者：施喆刘会雪杨晓达北京大学医学部天然药物及仿生药物国家重点实验室药学院化学生物学系北京100191

Vanadium compounds show potential in diabetes and cancer treatment, although the toxicity remains a great concern. Previous studies have shown that vanadium-induced oxidative stress affecting mitochondrial function is intensively responsible for the toxicity. In this work, we investigated the effects of the vanadium compounds sodium metavanadate （NaVO3） and vanadyl acetylacetonate （VO（acac）2） on mitochondrial ROS generation and respiratory complex activities. The experimental results showed that vanadium compounds affected the ROS generation and complex activities in different patterns depending on the chemical species. NaVO3 inhibited mitochondrial complexes Ⅰ and Ⅱ activities and stimulated ROS generation at low concentration range; while VO（acac）2 promoted complex Ⅱ activity but resulted in electron leakage from the complex Ⅰ-involved pathway. The present results provide new evidence for understanding the toxicity of antidiabetic vanadium compounds.

关键词： Vanadium species ROS generation Respiratory complex activity Mitochondria

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