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Geldanamycin inhibits proliferation and motility of Her2/neu-overexpressing SKBr3 breast cancer cells

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Journal of Pharmaceutical Analysis 2008年第4期20卷 235-241页

作者：任予王珂何建军陈武科马清涌 Department of Oncology the First Affiliated Hospital Medical School of Xi'an Jiaotong University Department of Gastroenterology the First Affiliated Hospital Medical School of Xi'an Jiaotong University

Objective Benzoquinone ansamycin antibiotic, Geldanamycin (GA), is a new anticancer agent that could inhibit Hsp90 by occupying its NH2-terminal ATP-binding site. This study was to investigate the antitumor efficacy of GA on Her2/neu tyrosine kinase overexpressing human breast cancer cell line SKBr3. Methods The degradation of Her2/neu tyrosine kinase was analyzed by Western blotting, the proliferation index was determined by MTT assay, cell cycle distribution was detected by flow cytometry, Cyclin D1 mRNA transcription was measured by RT-PCR and real-time PCR, and cell motility was evaluated by the cell culture insert model. Results GA induced a dose-and a time-dependent degradation of the Her2/neu tyrosine kinase protein and concurrently, the inhibition of cancer cell proliferation. The antitumor effects mediated by GA included: GA treatment decreased the survival rates of cancer cells, and led to a dose-dependent G1 arrest. Furthermore, this antitumor effect was proved to be related to declined transcription of Cyclin D1. Concurrently, the motility of cancer cells was reduced by GA. Conclusion GA treatment could induce the degradation of Her2/neu tyrosine kinase efficiently, inhibit cancer cell proliferation and reduce motility in Her2/neu tyrosine kinase overexpressed human breast cancer cell line SKBr3.

关键词： Her2/neu Geldanamycin cyclin D1 breast cancer

Geldanamycin产生菌生物合成相关基因的克隆与分析

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中国抗生素杂志 2002年第1期27卷 13-17,27页

作者：高群杰尚广东杨樱孙桂芝王以光陶佩珍娄志贤姚天爵中国医学科学院中国协和医科大学医药生物技术研究所北京100050

目的　从 Geldanamycin产生菌吸水链霉菌 (S.hygroscopicus)中克隆生物合成基因 ,为阐明生物合成机制及改造其结构奠定基础。方法　以链霉菌 /大肠埃希氏菌穿梭 cosmids p KC5 0 5为载体构建了插入片段为 2 0～ 30 kb的 S.hygroscopicus... 详细信息

目的　从 Geldanamycin产生菌吸水链霉菌 (S.hygroscopicus)中克隆生物合成基因 ,为阐明生物合成机制及改造其结构奠定基础。方法　以链霉菌 /大肠埃希氏菌穿梭 cosmids p KC5 0 5为载体构建了插入片段为 2 0～ 30 kb的 S.hygroscopicus总 DNA文库。以利福霉素中与 3-氨基 - 5 -羟基苯甲酸 (AHBA)合成相关基因为探针 ,经菌落杂交 ,Southern杂交筛选同源基因片段。测序结果与 Genbank进行同源性比较分析 ,并以attp- 噬菌体载体 KC5 15利用基因阻断实验对克隆的基因片段进行功能鉴定。结果　构建的基因文库含重组基因比率高、基因组覆盖率高 ,稳定性好。经同源基因探针杂交 ,从文库中筛选出 9个阳性 cosmids克隆p CGB2 0、p CGB2 6、p CGB2 8、p CGB2 9、p CGB36、p CGB45、p CGB49、p CGB6 3、p CGB75。测序分析表明 ,cosmidp CGB2 0中 Bam HI- Bam HI 8kb片段两端的不完整 ORF编码蛋白与竹桃霉素 (oleandomycin) PKS Module 5、Module 6 (一致性为 79% )和红霉内酯合成酶 ORF2 (一致性为 75 % )、ORF1(一致性为 73% )、ORF3(一致性为 70 % )高度同源 ;Bam HI- Bam HI3kb片段一端与编码类结核分枝杆菌的磷酸吡哆醛依赖的氨基转移酶家族中半胱氨酸脱硫酶的 DNA有同源性 ,该家族与 AHBA合成酶关系密切。

关键词： Geldanamycin 生物合成基因基因文库基因阻断安莎霉素类抗生素

Geldanamycin Combination with Colcemid Induces Mitotic Arrest through Stabilization of bubR1 Mitotic Kinase in Human Tumor Cells

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Journal of Cancer Therapy 2013年第3期4卷 709-719页

作者： Pitke Vikrant Vinay Lebaka Prasanna Anjaneya Reddy Jonnala Ujwal Kumar Sugunan Sreedevi Upasana Sarangi Amere Subbarao Sreedhar CSIR—Centre for Cellular and Molecular Biology Hyderabad India

Mitosis-targeted anti-cancer therapies gained much attention in recent years. However, lack of tumor selectivity poses limitations to the current anti-mitotic drugs to be used as broad-spectrum anti-cancer agents. In this study, we show that combination treatment of colcemid, an inhibitor of microtubule polymerization with Geldanamycin, an inhibitor of cancer chaperone, Hsp90 irreversibly targets mitosis through mitotic kinase bubR1 stabilization. When the individual and combination drugs treatments were tested against tumor cells (IMR-32 and HeLa) and non-tumor cells (SRA01), the combination treatment showed significant increase in cytotoxicity only in tumor cells followed by G2/M cell cycle block. The IMR-32 cells showed enhanced cytotoxicity in response to combination treatments, compared to HeLa cells. Further studies revealed that the G2/M arrest in IMR-32 correlates with both increased bubR1 nuclear localization and metaphase arrest. The siRNA knockdown of bubR1 has decreased tumor cell response to Geldanamycin suggesting Hsp90-dependent regulation of bubR1. The combination treatment also showed inactivation of non-canonical β-catenin signaling suggesting inhibition of cancer growth. In addition, the combination treatment has significantly affected the distribution and functions of bubR1 downstream mitotic kinases such as aurks and plk1 indicating the combinatorial attack of combination treatment. In conclusion, we demonstrate that colcemid and GA combination treatment compromises the division potential of tumor cells interfering with the mitosis through bubR1 kinase.

关键词： Hsp90 Geldanamycin bubR1 Cell Cycle Tumor Cells

HSP90的抑制剂Geldanamycin对乳腺癌细胞侵袭、转移能力的影响

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重庆医科大学学报 2006年第1期31卷 55-57,73页

作者：罗红霞邓华瑜郑维萍重庆医科大学基础医学院病理生理教研室重庆400016

目的:探讨H SP90抑制剂Geldanam ycin(GA)对高转移性乳腺癌细胞株M DA-MB-231、MDA-M B-435s侵袭、转移能力的影响。方法:噻唑兰比色(M TT)法检测两株细胞对人工基底膜(Matrigel)的粘附能力变化;TranswellCham ber体外侵袭运动实验研究G... 详细信息

目的:探讨H SP90抑制剂Geldanam ycin(GA)对高转移性乳腺癌细胞株M DA-MB-231、MDA-M B-435s侵袭、转移能力的影响。方法:噻唑兰比色(M TT)法检测两株细胞对人工基底膜(Matrigel)的粘附能力变化;TranswellCham ber体外侵袭运动实验研究GA处理前后M DA-M B-231、M DA-M B-435s细胞侵袭、运动能力的改变。结果:GA处理后的M DA-M B-231和M DA-MB-435s细胞的粘附、侵袭、运动能力与未处理组细胞相比均明显下降,差异具有显著性(P<0.05和P<0.01)。结论:H SP90抑制剂Geldanam ycin(GA)能够明显抑制乳腺癌细胞株M DA-MB-231、MDA-M B-435s粘附、侵袭和运动能力。

关键词：乳腺癌细胞 Geldanamycin HSP90

热休克蛋白90抑制剂Geldanamycin的抗肿瘤作用研究进展

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药学学报 2001年第9期36卷 716-720页

作者：廖志勇甄永苏中国医学科学院中国协和医科大学医药生物技术研究所北京100050

Geldanamycin(GDM)属于苯醌安莎霉素类抗生素,其衍生物17-烯丙胺-17-脱甲氧格尔德霉素.

关键词：格尔德霉素热休克蛋白90抑制剂生化调节剂 Geldanamycin 抗肿瘤作用

Geldanamycin增强顺铂的抗肿瘤作用

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癌症 2000年第8期19卷 731-734页

作者：廖志勇张胜华甄永苏中国医学科学院中国协和医科大学医药生物技术研究所北京100050

研究抗生素苯醌安莎霉素(Geldanamycin ,GDM)对人肝癌BEL 7402细胞周期的影响和联合应用顺铂 (CDDP)的体外体内抗肿瘤作用。方法 :采用MTT法检测药物的生长抑制作用 ,[3H] TdR掺入法测定DNA合成抑制作用 ,流式细胞术分析细胞周期 ,小鼠... 详细信息

研究抗生素苯醌安莎霉素(Geldanamycin ,GDM)对人肝癌BEL 7402细胞周期的影响和联合应用顺铂 (CDDP)的体外体内抗肿瘤作用。方法 :采用MTT法检测药物的生长抑制作用 ,[3H] TdR掺入法测定DNA合成抑制作用 ,流式细胞术分析细胞周期 ,小鼠移植性肝癌H22模型研究药物单用或联合应用时的体内抗肿瘤作用。结果 :MTT法测得GDM对BEL 7402细胞的生长抑制IC50为0 28μmol/L。GDM处理BEL 7402细胞4h ,抑制DNA合成的IC50为14μmol/L。1 0、10μmol/LGDM处理BEL 7402细胞24h后S期细胞比例明显下降 ,并持续到48h ;0 1、1 0、10μmol/L的GDM引起G2/M期的明显阻断 ,24h时达高峰值 ,48h后开始回复。体外0 1μmol/L和0 2μmol/LGDM均增强CDDP对BEL 7402细胞的细胞毒作用。小鼠移植肝癌H22模型中 ,单用1 5mg/kgCDDP组两批试验的抑瘤率均为73 % ,顺铂联用0 38mg/kgGDM两批试验的抑瘤率分别为89 %和82% ,两者有显著性差异(P<0 05) ,其CDI值分别为0 41和0 72。结论

关键词： Geldanamycin 顺铂肿瘤药物疗法

Anti-Inflammatory Activity of Geldanamycin and Its Derivatives in LPS-Induced RAW 264.7 Cells

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Advances in Microbiology 2019年第4期9卷 398-421页

作者： Thongchai Taechowisan Winyou Puckdee Watcharee Waratchareeyakul Waya S. Phutdhawong Department of Microbiology Faculty of Science Silpakorn University Nakhon Pathom Thailand Department of Biology Faculty of Science and Technology Rambhai Barni Rajabhat University Chanthaburi Thailand Department of Chemistry Faculty of Science and Technology Rambhai Barni Rajabhat University Chanthaburi Thailand Department of Chemistry Faculty of Science Silpakorn University Nakhon Pathom Thailand

Geldanamycin (1) had been isolated as a major compound from Streptomyces zerumbet W14;an endophyte of Zingiber zerumbet (L.) Smith. Two new Geldanamycin derivatives;17-(tryptamine)-17-demethoxyGeldanamycin (2) and 17-(5’-methoxytryptamine)-17-demethoxyGeldanamycin (3) were synthe- sized and their anti-inflammatory activity was evaluated in LPS-induced macrophage RAW 264.7 cells by investigating their effects on the inhibition of production of NO, PGE2, TNF-α, IL-1β, IL-6 and IL-10. The data obtained were consistent with the modulation of TNF-α, IL-1β, IL-6, IL-10 production by these derivatives at concentration of 1 to 5 μg/ml. A similar effect was also observed when LPS-induced NO release and PGE2 production were tested. The inhibitory effects were shown in concentration-dependent manners. From the obtained results, it was concluded that two new gelda- namycin derivatives possess anti-inflammatory activity on LPS-induced RAW 264.7 cells. They could be useful for the management of inflammatory diseases.

关键词： Anti-Inflammatory Activity Geldanamycin Derivatives Streptomyces zerumbet RAW 264.7 Cells

Docking of Human Heat Shock Protein 90 with Selenoderivatives of Geldanamycin

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Crystal Structure Theory and Applications 2019年第2期8卷 13-27页

作者： Jason T. Kilembe Albert S. Lundemba Dikima D. Bibelayi Glodi M. Ndefi Juliette Pradon Zéphyrin G. Yav Department of Chemistry University of Kinshasa Kinshasa Democratic Republic of Congo The Cambridge Crystallographic Data Centre Cambridge UK

The interference of human heat shock protein 90 (HSP90) in many signalling networks associated with cancer progression makes it an important drug target. In the present work, we investigated the binding ability of 9 selenoderivatives of Geldanamycin (GMDSe) at the N-terminal domain of HSP90 derived from Protein Data Bank (PDB code: 1YET) based on ligand-protein docking. All selenoderivatives interacted positively with HSP90, yet the binding strength decreased when replacing monovalent oxygen in position 1 (GMDSe1) or 9 (GMDSe9). Hydrogen-bonding and lipophilic interactions between selenoderivatives and amino acid residues in the inhibitor site of HSP90 were thermodynamically the main forces driving the binding stability. Molecular electrostatic potential surfaces of the selenoderivatives showed marked non polar areas, which were probably involved in the lipophilic interactions with the hydrophobic residues of amino acids. Interestingly, the amino acid residues forming the hydrogen bonds with GMD were also involved in the hydrogen-bonding interactions with the selenoderivatives. Moreover, HSP90 interacted with the GMDSe6 and GMDSe7 selenoderivatives stronger than with GMD, while maintaining lipophilic interactions and hydrogen bonds with amino acid residues like Asp93, which are catalytically crucial for therapeutic properties of HSP90 inhibitors. This finding should guide further studies of pharmacophore properties of GMD selenoderivatives in order to explore their therapeutic properties. It is noteworthy that selenium has been suggested to reduce the risk of various types of cancers.

关键词： 1YET Geldanamycin Selenoderivatives Cambridge Structural Database Binding Energy Molecular Electrostatic Potential (MEP)

Geldanamycin增强化疗药物的抗肿瘤作用

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Geldanamycin增强化疗药物的抗肿瘤作用