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Maeva Dufies, Damien Ambrosetti, Sonia Boulakirba, Anne Calleja, Coline Savy, Nathan Furstoss, Marwa Zerhouni, Julien Parola, Lazaro Aira-Diaz, Sandrine Marchetti, Francois Orange, Sandra Lacas-Gervais, Frederic Luciano, Arnaud Jacquel, Guillaume Robert, Gilles Pagès, Patrick Auberger
Polo-like kinases (Plks) define a highly conserved family of Ser/Thr kinases with crucial roles in the regulation of cell division. Here we show that Plk1 is cleaved by caspase 3, but not by other caspases in different hematopoietic cell lines treated with competitive inhibitors of the ATP-binding pocket of Plk1. Intriguingly, Plk1 was not cleaved in cells treated with Rigosertib, a non-competitive inhibitor of Plk1, suggesting that binding of the inhibitor to the ATP binding pocket of Plk1 triggers a conformational change and unmasks a cryptic caspase 3 cleavage site on the protein...
February 16, 2018: Oncotarget
Jianwen Dong, Soon Young Park, Nghi Nguyen, Ravesanker Ezhilarasan, Emmanuel Martinez-Ledesma, Shaofang Wu, Verlene Henry, Yuji Piao, Ningyi Tiao, David Brunell, Clifford Stephan, Roel Verhaak, Erik Sulman, Veerakumar Balasubramaniyan, John F de Groot
Background: Despite the availability of hundreds of cancer drugs, there is insufficient data on the efficacy of these drugs on the extremely heterogeneous tumor cell populations of glioblastoma (GBM). Results: The PKIS of 357 compounds was initially evaluated in 15 different GSC lines which then led to a more focused screening of the 21 most highly active compounds in 11 unique GSC lines using HTS screening for cell viability. We further validated the HTS result with the second-generation PLK1 inhibitor volasertib as a single agent and in combination with ionizing radiation (IR)...
February 13, 2018: Oncotarget
Jianping Hu, Yingqing Wang, Yanlian Li, Danyan Cao, Lin Xu, ShanShan Song, Mohammadali Soleimani Damaneh, Jian Li, Yuelei Chen, Xin Wang, Lin Chen, Jingkang Shen, Zehong Miao, Bing Xiong
Recently, several kinase inhibitors were found to also inhibit bromodomains, providing a new strategy for the discovery of bromodomain inhibitors. Along this line, starting from PLK1-BRD4 dual inhibitor BI-2536, we discovered a new series of dihydroquinoxalin-2(1H)-one with aniline and indoline WPF binders as selective BRD4 inhibitors. They showed better BRD4-BD1 potency and negligible PLK1 kinase activity comparing with BI-2536. Additionally, dihydroquinoxalin-2(1H)-ones containing indoline group showed profound activities in molecular and cellular based assays...
February 24, 2018: European Journal of Medicinal Chemistry
Deepesh Kumar Gupta, Jian Du, Siamak A Kamranvar, Staffan Johansson
Previous studies have shown that cytokinetic abscission at the end of mitosis is executed by the ESCRT machinery in mammalian cells, and that the process is dependent on adhesion-induced integrin signalling via a FAK-PLK1-CEP55-TSG101/Alix-CHMP4B pathway. The present study identified an alternative abscission mechanism driven by mechanical force. In the absence of integrin signals (non-adherent conditions), cytokinesis in non-transformed human fibroblasts proceeds to CEP55 accumulation at the midbody, but after prolonged time (>3 hours) the major midbody components Aurora B, MKLP1 and CEP55 were no longer detected in the area...
February 6, 2018: Oncotarget
Ayaka Okamoto, Tomohiro Asai, Yusuke Hirai, Kosuke Shimizu, Hiroyuki Koide, Tetsuo Minamino, Naoto Oku
Triple-negative breast cancer is one of intractable cancers that are not sensitive to the treatment with existing molecular-targeted drugs. Recently, there has been much interest in RNA interference-mediated treatment of triple-negative breast cancer. In the present study, we have developed lipid nanoparticles encapsulating siRNA (LNP-siRNA) decorated with an Fab' antibody against heparin-binding EGF-like growth factor (αHB-EGF LNP-siRNA). αHB-EGF LNP-siRNA targeting polo-like kinase 1 (PLK1) was prepared and evaluated for its anticancer effect using MDA-MB-231 human triple-negative breast cancer cells overexpressing HB-EGF on their cell surface...
March 5, 2018: Molecular Pharmaceutics
Matheus de Freitas Silva, Letícia Ferreira Coelho, Isadora Mitestainer Guirelli, Rodrigo Machado Pereira, Guilherme Álvaro Ferreira da Silva, Graciana Y Graravelli, Renato de Oliveira Horvath, Ester Siqueira Caixeta Nogueira, Marisa Ionta, Claudio Viegas
Curcumin (1) and resveratrol (2) are bioactive natural compounds that display wide pharmacological properties, including antitumor activity. However, their clinical application has been limited due to their low solubility and bioavailability. Nevertheless, independent studies have considered these compounds as interesting prototypes for developing new chemical structures useful for anticancer therapy. Here in, we report the synthesis of novel curcumin-like hydrazide analogues (3a and 3b), and a series of curcumin-resveratrol hybrid compounds (4a-f), and the evaluation of their cytotoxic potential on three tumor cell lines MCF-7 (breast), A549 (lung), and HepG2 (liver)...
March 1, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Ying Shi, Sicheng Guo, Ying Wang, Xin Liu, Qingwei Li, Tiesong Li
Prohibitin 2(PHB2) is a member of the SFPH trans-membrane family proteins. It is a highly conserved and functionally diverse protein that plays an important role in preserving the structure and function of the mitochondria. In this study, the lamprey PHB2 gene was expressed in HeLa cells to investigate its effect on cell proliferation. The effect of Lm-PHB2 on the proliferation of HeLa cells was determined by treating the cells with pure Lm-PHB2 protein followed by MTT assay. Using the synchronization method with APC-BrdU and PI double staining revealed rLm-PHB2 treatment induced the decrease of both S phase and G0/G1 phase and then increase of G2/M phase...
March 2, 2018: Scientific Reports
Xiao-Jiao Li, Jin-Shu Pang, Yao-Mei Li, Farah Abdirahman Ahmed, Rong-Quan He, Jie Ma, Fu-Chao Ma, Gang Chen
OBJECTIVE: An increasing number of studies have confirmed that survivin (BIRC5) plays essential roles in ovarian cancer. Nevertheless, inconsistent or controversial results exist in some studies. In the present study, we sought to determine the clinical significance of survivin and its potential molecular pathways. METHODS: The correlation between survivin (BIRC5) expression and diagnostic value, prognostic value and clinicopathological features was assessed by meta-analysis with more than 4000 patients from literature, GEO and TCGA...
January 2, 2018: Pathology, Research and Practice
Chunhui Ruan, Lisha Liu, Qingbing Wang, Xinli Chen, Qinjun Chen, Yifei Lu, Yu Zhang, Xi He, Yujie Zhang, Qin Guo, Tao Sun, Chen Jiang
An ideal gene-carrying vector is supposed to exhibit outstanding gene condensing capability with positively charged macromolecules to protect the carried gene during in vivo circulation, and a rapid dissociation upon microenvironmental stimuli at the aimed sites to release the escorted gene. Currently, it still remains a challenge to develop an ideal gene carrier with efficient transfection ability and meanwhile low toxicity for clinical applications. Herein, we innovatively introduced a ROS-biodegradable boric acid ester linkage in elaborating the design of gene carrier...
March 2, 2018: ACS Applied Materials & Interfaces
Maria Sol Brassesco, Julia Alejandra Pezuk, Karina Bezerra Salomao, Gabriela Molinari Roberto, Carlos Alberto Scrideli, Luiz Gonzaga Tone
Over the last decade, the inhibition of PLK1 has proven potent antiproliferative activity in vitro. However, the effectiveness of most synthetic targeted drugs has not translated into clinics. Herein, we investigated the in vitro effects of two second-generation PLK1 inhibitors BI 6727 and GSK461364 in breast cancer cell lines as monotherapy or in combination with other drugs or ionizing radiation. MATERIAL AND METHODS: Cell survival was analyzed through XTT®, clonogenicity and caspase-3 activation assays were also studied, and drug interactions analyzed through a nonlinear regression of a sigmoid dose response model...
February 28, 2018: Anti-cancer Agents in Medicinal Chemistry
Geun-Hyoung Ha, Dong-Young Kim, Eun-Kyoung Breuer, Chung Kwon Kim
BACKGROUND/AIM: Breast cancer is the most common malignant cancer type in women, and triple-negative breast cancer (TNBC) is an extremely aggressive subtype of breast cancer with poor prognosis rates. The present study investigated the antitumor effect of polo-like kinase 1 (PLK1) inhibitor in combination with the tankyrase-1 (TNKS1) inhibitor on TNBC cells. MATERIALS AND METHODS: We evaluated the antitumor effects of combination therapy with PLK1 and TNKS1 inhibitor using cell viability analysis, apoptosis assay and transwell assay for cell invasion and migration in TNBC cells...
March 2018: Anticancer Research
Ines J de Castro, Raquel Sales Gil, Lorena Ligammari, Maria Laura Di Giacinto, Paola Vagnarelli
Micronuclei (MN) arise from chromosomes or fragments that fail to be incorporated into the primary nucleus after cell division. These structures are a major source of genetic instability caused by DNA repair and replication defects coupled to aberrant Nuclear Envelope (NE). These problems ultimately lead to a spectrum of chromosome rearrangements called chromothripsis, a phenomenon that is a hallmark of several cancers. Despite its importance, the molecular mechanism at the origin of this instability is still not understood...
January 30, 2018: Oncotarget
Sabine A G Cuijpers, Alfred C O Vertegaal
Cell division is tightly regulated to disentangle copied chromosomes in an orderly manner and prevent loss of genome integrity. During mitosis, transcriptional activity is limited and post-translational modifications (PTMs) are responsible for functional protein regulation. Essential mitotic regulators, including polo-like kinase 1 (PLK1) and cyclin-dependent kinases (CDK), as well as the anaphase-promoting complex/cyclosome (APC/C), are members of the enzymatic machinery responsible for protein modification...
February 24, 2018: Trends in Biochemical Sciences
Ke Liu, Lijing Fang, Haiyan Sun, Zhengyin Pan, Jianchao Zhang, Juntao Chen, Ximing Shao, Wei Wang, Yuanyan Tan, Zhihao Ding, Lijiao Ao, Chunlei Wu, Xiaoqi Liu, Huashun Li, Rui Wang, Wu Su, Hongchang Li
The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst conjugate, PIP3, targeted to specific DNA sequence in the Plk1 promoter...
February 26, 2018: Molecular Cancer Therapeutics
Chunguang Li, Liangtao Luo, Sheng Wei, Xiongbiao Wang
Invasive ductal carcinoma (IDC) is a common histological type of breast cancer. The aim of this study was to identify the potential crucial genes associated with IDC and to provide valid biological information for further investigations. The gene expression profiles of GSE10780 which contained 42 histologically normal breast tissues and 143 IDC tissues were downloaded from the GEO database. Functional and pathway enrichment analysis of differentially expressed genes (DEGs) were performed and protein-protein interaction (PPI) network was analyzed using Cytoscape...
January 23, 2018: Oncotarget
HaiYang Wang, Min Ho Choe, In-Won Lee, Suk Namgoong, Jae-Sung Kim, Nam-Hyung Kim, Jeong Su Oh
No abstract text is available yet for this article.
February 21, 2018: Development
Wen-Jie Huang, Yunchao Wang, Songsong Liu, Jiali Yang, Shi-Xiang Guo, Lijiang Wang, Huaizhi Wang, Ying-Fang Fan
Circular RNAs (CircRNAs) are a novel type of endogenous noncoding RNAs that regulate target gene expression by interacting with microRNA (miRNA). Emerging evidence shows that dysregulation of circRNAs plays important roles in biological and pathological processes, including cancer development and progression. The functional role of circRNA in PDAC (pancreatic ductal adenocarcinoma) remains to be investigated. In this study, high throughput microarray assay revealed that hsa_circ_0000977 was aberrantly up-regulated in pancreatic cancer tissues; this was also validated by qRT-PCR...
February 15, 2018: Cancer Letters
Yue Zhang, Kewei Ren, Xiaobo Zhang, Zhicong Chao, Yuqin Yang, Deju Ye, Zhihui Dai, Ying Liu, Huangxian Ju
RNA interference (RNAi) has become an appealing therapeutic approach for cancer and other diseases. One key challenge is the effective protection of these small fragile biomolecules against complicated physiological environments as well as efficient on-demand release. Here we design a photo-tearable polymer tape close-wrapped nanocapsule for efficient NIR modulated siRNA delivery. The photo-tearable nanocapsules comprise core-shell upconversion nanoparticles (UCNPs) coated with mesoporous silica layer for loading of photosensitizer hypocrellin A (HA) and small interfering RNA (siRNA) against polo-like kinase 1 (PLK1), and covalently bound thin membranes of polyethylene glycol (PEG) via a synthesized photocleavable linker (PhL)...
February 9, 2018: Biomaterials
Ji Yea Kim, So Young Kim, Hong Seo Choi, Min Kyu Kim, Hyun Min Lee, Young-Joo Jang, Chun Jeih Ryu
Progesterone receptor membrane component 1 (PGRMC1) is a multifunctional heme-binding protein involved in various diseases, including cancers and Alzheimer's disease. Previously, we generated two monoclonal antibodies (MAbs) 108-B6 and 4A68 against surface molecules on human pluripotent stem cells (hPSCs). Here we show that PGRMC1 is the target antigen of both MAbs, and is predominantly expressed on hPSCs and some cancer cells. PGRMC1 is rapidly downregulated during early differentiation of hPSCs. Although PGRMC1 knockdown leads to a spread-out morphology and impaired self-renewal in hPSCs, PGRMC1 knockdown hPSCs do not show apoptosis and autophagy...
February 14, 2018: Scientific Reports
Pablo R Duchowicz
A structurally diverse dataset of 530 polo-like kinase-1 (PLK1) inhibitors is compiled from the ChEMBL database and studied by means of a conformation-independent quantitative structure-activity relationship (QSAR) approach. A large number (26,761) of molecular descriptors are explored with the main intention of capturing the most relevant structural characteristics affecting the bioactivity. The structural descriptors are derived with different freeware, such as PaDEL, Mold², and QuBiLs-MAS; such descriptor software complements each other and improves the QSAR results...
February 14, 2018: Cells
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