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Transient HSP90 inhibition enhances the sensitivity of mantle cell lymphoma to poly(ADP-ribose)polymerase(parp)inhibitors

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Genes & Diseases 2023年第5期10卷 1791-1794页

作者： Chaowen Shi Dewan Ren Yufeng Gao Ya-Mei Dang Zhigang Tu Hanqing Liu School of Life Sciences Jiangsu UniversityZhenjiangJiangsu 212013China School of Pharmacy Jiangsu UniversityZhenjiangJiangsu 212013China Department of Pathology Gansu Provincial HospitalLanzhouGansu 730000China

Mantle cell lymphoma(MCL)is an aggressive subtype of non-Hodgkin lymphoma(NHL)characterized by the overexpression of cyclin D1 and deregulated cell cycle.1 Ganetespib(STA-9090),a second-generation HSP90 inhibitor,dramatically disrupted oncogenic cellular processes resulting in the inhibition of client protein-derived tumors in preclinical studies.2 The synthetic lethal strategy using poly(ADP-ribose)polymerase(parp)inhibitors(parpis)has been reported as a powerful therapeutic intervention in MCL and their effectiveness can be increased by a deficiency in DNA damage repair(DDR),especially homologous recombination deficiency.3 Since we found earlier that transient ganetespib treatment can induce defects in DDR,we hypothesized that ganetespib treatment can possibly enhance the sensitivity of MCL cells to parpis and HSP90 and parp is can be demonstrated as promising combination therapies for MCL.

关键词： lymphoma parp sized

ZRANB1 is an NBS1 deubiquitinase and a potential target to overcome radioresistance and parp inhibitor resistance in triple-negative breast cancer

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Genes & Diseases 2023年第5期10卷 1739-1742页

作者： Ying Mei Qinglei Hang Hongqi Teng Fan Yao Mei-Kuang Chen Mien-Chie Hung Yutong Sun Li Ma Department of Experimental Radiation Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences HoustonTX 77030USA Hubei Hongshan Laboratory College of Biomedicine and HealthCollege of Life Science and TechnologyHuazhong Agricultural UniversityWuhanHubei 430070China

Poly(ADP-ribose)polymerase inhibitors(parpi)are used to treat ovarian cancer and triple-negative breast cancer(TNBC)with defective homologous recombination repair ***,de novo and acquired parpi resistance limits clinical benefits.1 The MRE11-RAD50-NBS1(MRN)complex mediates the sensing,processing,and signaling of DNA double-strand breaks(DSBs)and plays important roles in the efficacy of parpi and radiation treatment,2 and yet the mechanisms for the regulation and degradation of the MRN complex are not well ***1,also known as Trabid,is a breast cancer-promoting deubiquitinase that preferentially cleaves K29-,K33-,and K63-linked ubiquitin chains,3 but its role in therapy resistance remains unknown.

关键词： ubiquitin resistance parp

Nanoengineered Gallium Ion Incorporated Formulation for Safe and Efficient Reversal of parp Inhibition and Platinum Resistance in Ovarian Cancer

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Research 2023年第3期2023卷 793-808页

作者： Yangyang Li Yixuan Cen Mengyan Tu Zhenzhen Xiang Sangsang Tang Weiguo Lu Hongbo Zhang Junfen Xu Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases Women’s HospitalZhejiang University School of MedicineHangzhouZhejiangChina Department of Gynecologic Oncology Women’s HospitalZhejiang University School of MedicineHangzhou 310006ZhejiangChina Women’s Reproductive Health Laboratory of Zhejiang Province Women’s HospitalZhejiang University School of MedicineHangzhou 310006ZhejiangChina Cancer Center Zhejiang UniversityHangzhou 310058ZhejiangChina Pharmaceutical Sciences Laboratory Åbo Akademi UniversityTurku FI-20520Finland Turku Bioscience Centre University of Turku andÅbo Akademi UniversityTurku FI-20520Finland

Platinum-based chemotherapy remains the main systemic treatment of ovarian cancer(OC).However,the inevitable development of platinum and poly(adenosine diphosphate-ribose)polymerase inhibitor(parpi)resistance is associated with poor outcomes,which becomes a major obstacle in the management of this *** present study developed“all-in-one”nanoparticles that contained the parpi olaparib and gallium(Ga)(III)(olaparib-Ga)to effectively reverse parpi resistance in platinum-resistant A2780-cis and SKOV3-cis OC cells and in SKOV3-cis tumor ***,the olaparib-Ga suppressed SKOV3-cis tumor growth with negligible ***,the suppression effect was more evident when combining olaparib-Ga with cisplatin or carboplatin,as evaluated in A2780-cis and SKOV3-cis ***,the combined treatment induced DNA damage,which elicited the activation of ataxia telangiectasia mutated(ATM)/AMT-and Rad3-related(ATR)checkpoint kinase 1(Chk1)/Chk2 signal transduction *** led to the arrest of cell cycle progression at S and G2/M phases,which eventually resulted in apoptosis and cell death due to unrepairable DNA *** addition,effective therapeutic responses to olaparib-Ga and cisplatin combination or olaparib-Ga and carboplatin combination were observed in SKOV3-cis tumor-bearing animal ***,the present findings demonstrate that olaparib-Ga has therapeutic implications in platinum-resistant OC cells,and the combination of olaparib-Ga with cisplatin or carboplatin may be promising for treating patients with OC who exhibit resistance to both parpi and platinum.

关键词： platinum parp eventually

BRCA1,parp,and 53BP1:conditional synthetic lethality and synthetic viability

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分子细胞生物学报:英文版 2011年第1期3卷 66-74页

作者： Amal Aly Shridar Ganesan Cancer Institute of New Jersey Robert Wood Johnson Medical School-UMDNJ195 Little Albany StreetNew BrunswickNJ 08903USA

BRCA1 plays a critical role in the regulation of homologous recombination(HR)-mediated DNA double-strand break ***1-deficient cancers have evolved to tolerate loss of BRCA1 *** renders them vulnerable to agents,such as parp inhibitors,that are conditionally‘synthetic lethal’with their underlying repair *** studies demonstrate that BRCA1-deficient cells may acquire resistance to these agents by partially correcting their defect in HR-mediated repair,either through reversion mutations in BRCA1 or through‘synthetic viable’loss of *** findings and their clinical implications will be reviewed in this article.

关键词： DNA repair BRCA1 53BP1 parp

Relationship of PARG with parp,VEGF and b-FGF in Colorectal Carcinoma

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Chinese Journal of Cancer Research 2009年第2期21卷 135-141页

作者： Ling Lin Jia Li Ya-lan Wang Xiao Lin Department of Pathology Molecular Medicine and Cancer Research Center Chongqing Medical UniversityChongqing 400016 China

Objective： To investigate the relationship of poly（ADP-ribose）glycohydrolase（PARG） with poly （ADP-ribose） polymerase（parp）, vascular endothelial growth factor （VEGF） and basic fibroblast growth factor（b-FGF） in colorectal carcinoma（CRC）. Methods： Immunohistochemical analysis was used to detect PARG, parp, VEGF and b-FGF in human colorectal carcinoma. Flow cytometry was used to detect PARG and parp in murine CT26 cell line. Gallotannin （GLTN） was served as PARG inhibitor. Results： The individual positive rates of PARG, PARE VEGF and b-FGF were 55.81%（24/43）, 97.67%（42/43）, 79.07%（34/43） and 81.40%（35/43）, respectively, which were significantly higher than those of control group. The positive PARG was correlated to parp（r=0.3703, P〈0.05） and b-FGF （r=0.4838, P〈0.05）. The positive parp was correlated to VEGF （r=0.3968, P〈0.05） and b-FGF （r=0.5610, P〈0.05）. Both PARG and parp were expressed in CT26 cells. The positive staining rates of PARG and parp in GLTN-treated group were 7.3% and 52.38%, respectively. They were markedly reduced than those of control group （55.41% and 95.28%, P〈0.01, n=10000）. Conclusion： The data suggest that PARG expression probably plays a role for VEGF and b-FGF expression in colorectal carcinoma.

关键词： PARG parp VEGF b-FGF Colorectal carcinoma

Design,synthesis and biological evaluation of novel phthalazinone acridine derivatives as dual parp and Topo inhibitors for potential anticancer agents

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Chinese Chemical Letters 2020年第2期31卷 404-408页

作者： Qiuzi Dai Jiwei Chen Chunmei Gao Qinsheng Sun Zigao Yuan Yuyang Jiang Department of Chemistry Tsinghua UniversityBeijing 100084China The State Key Laboratory of Chemical Oncogenomics Key Laboratory of Chemical BiologyThe Graduate School at ShenzhenTsinghua UniversityShenzhen 518055China College of Chemistry and Chemical Engineering Shenzhen UniversityShenzhen 518060China Department of Pharmacology and Pharmaceutical Sciences School of MedicineTsinghua UniversityBeijing 100084China

In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual parp and Topo *** assays indicated that most of the compounds significantly inhibited multiple cancer cells *** addition,all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L,and also possessed good parp-1 inhibitory *** mechanistic studies showed that compound 9 a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 *** study suggested that 9 a inhibiting Topo and parp concurrently can be a potential lead compound for cancer therapy.

关键词： Topo parp Multitarget Acridines Antitumor bioactivity

基于parp和HDAC双靶点的化合物的合成及活性评价

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基于PARP和HDAC双靶点的化合物的合成及活性评价

作者：梁飞飞江苏海洋大学

学位级别：硕士

恶性肿瘤是一种涉及多个基因,发病机理高度复杂的疾病,目前临床使用的单靶点药物不能完全杀灭肿瘤细胞而且容易产生耐药性。组蛋白与DNA紧密缠绕形成染色质,在基因表达调控方面具有重要作用。组蛋白去乙酰化酶(HDACs)通过对组蛋白中的... 详细信息

恶性肿瘤是一种涉及多个基因,发病机理高度复杂的疾病,目前临床使用的单靶点药物不能完全杀灭肿瘤细胞而且容易产生耐药性。组蛋白与DNA紧密缠绕形成染色质,在基因表达调控方面具有重要作用。组蛋白去乙酰化酶(HDACs)通过对组蛋白中的赖氨酸残基进行乙酰化修饰,调控组蛋白与DNA的紧密程度,从而影响基因表达。如果组蛋白乙酰化水平异常则会导致恶性肿瘤的发生。聚ADP核糖聚合酶(parps)是一类DNA修复酶,它通过识别结构损伤的DNA位点而被激活,在DNA损伤修复与细胞凋亡中发挥着重要作用。有文献报道表明parp抑制剂和HDAC抑制剂具有良好的协同抗肿瘤效果。因此,基于parp/HDAC双靶点的研究具有较大的临床应用价值和科学意义。目的:以Vorinostat(SAHA)和Olaparib为结构母核,得到具有parp/HDAC双靶点活性的新化合物。方法:1)通过应用药效团拼接原理,设计了29个新化合物,再利用核磁共振波谱和质谱技术确定目标化合物的分子结构。2)初步评估了目标化合物的抗肿瘤活性。通过对HDAC1酶和parp1酶进行活性实验来检测目标化合物的酶活性抑制能力;在细胞水平检测了目标化合物对Hep G2细胞、BT 474细胞和HGC-27细胞的抗增殖活性。结论:本实验一共设计合成了29个新化合物,综合活性结果分析,所有的化合物均未表现出明显的parp1酶抑制活性,部分化合物表现出显著的HDAC1酶抑制活性。化合物B13是最优化合物,其不仅显示出最强的HDAC1酶抑制活性,酶活为34.74%,parp1酶活为84.07%,并且对3种人肿瘤细胞均显示出更强的抗增殖能力,其抗肿瘤机制值得进一步探索与研究。该论文有图15幅,表9个,参考文献87篇。

关键词：抗肿瘤药物双靶点抑制剂 HDAC parp

苯并呋喃类聚腺苷二磷酸核糖聚合酶(parp)抑制剂的设计、合成及活性研究

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有机化学 2013年第3期33卷 590-595页

作者：金秋辛敏行丛欣尤启冬江苏省药物分子设计与成药性优化重点实验室中国药科大学南京210009 江苏省抗肿瘤分子靶向药物重点实验室江苏先声药业有限公司南京210042

苯并呋喃类聚腺苷二磷酸核糖聚合酶(parp)是抗肿瘤治疗的一个有效靶点.本研究根据现有parp抑制剂的结构特征,设计并合成了未见文献报道的12个苯并呋喃类化合物,并进行了初步体外活性筛选.实验结果表明所合成的化合物均显示出一定的parp... 详细信息

苯并呋喃类聚腺苷二磷酸核糖聚合酶(parp)是抗肿瘤治疗的一个有效靶点.本研究根据现有parp抑制剂的结构特征,设计并合成了未见文献报道的12个苯并呋喃类化合物,并进行了初步体外活性筛选.实验结果表明所合成的化合物均显示出一定的parp抑制活性,其中化合物7c的活性与阳性对照药Veliparib活性相当,IC50为20.5 nmol·L-1。

关键词：抗肿瘤 parp 苯并呋喃合成

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parp和PKM2在肿瘤中的研究进展

中文科技期刊数据库（全文版）医药卫生 2023年第6期 28-30页

作者：蒋萍萍张继红北华大学附属医院吉林吉林132000

parp是处于真核细胞内的起到催化多聚ADP核糖基化的核酶,在DNA单链损伤修复方面有着积极意义。近年来,大量研究表明,parp的其中一员parp1可以在各种肿瘤物种中过度表达,其表达水平与各种类型的肿瘤病患的生存以及预后高度联系。丙酮酸激... 详细信息

parp是处于真核细胞内的起到催化多聚ADP核糖基化的核酶,在DNA单链损伤修复方面有着积极意义。近年来,大量研究表明,parp的其中一员parp1可以在各种肿瘤物种中过度表达,其表达水平与各种类型的肿瘤病患的生存以及预后高度联系。丙酮酸激酶(PK)为细胞糖酵解的核心组成,其可以催化烯醇丙酮酸得到丙酮酸同时可以释放一定的能量。PKM2则为PK的同工酶之一,是肿瘤能量代谢的转化标志,也已被佐证和多类肿瘤的形成有着极大的联系,基于控制PKM2活性,能够切实的管理以及引导肿瘤细胞能量代谢。parp1和PKM2在肿瘤中的表达和功能受到广泛关注。

关键词： parp PKM2 肿瘤