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https://www.readbyqxmd.com/read/28526367/discovery-of-a-novel-aminopyrazine-series-as-selective-pi3k%C3%AE-inhibitors
#1
Bernard Barlaam, Sabina Cosulich, Martina Fitzek, Hervé Germain, Stephen Green, Lyndsey L Hanson, Craig S Harris, Urs Hancox, Kevin Hudson, Christine Lambert-van der Brempt, Maryannick Lamorlette, Françoise Magnien, Gilles Ouvry, Ken Page, Linette Ruston, Lara Ward, Bénédicte Delouvrié
We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kβ and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration...
May 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28524703/computer-aided-prediction-and-cytotoxicity-evaluation-of-dithiocarbamates-of-9-10-anthracenedione-as-new-anticancer-agents
#2
M Stasevych, V Zvarych, V Lunin, N G Deniz, Z Gokmen, O Akgun, E Ulukaya, V Poroikov, T Gloriozova, V Novikov
Anticancer activity as an associated action for a series of dithiocarbamates of 9,10-anthracenedione was predicted using the PASS computer program and analysed with PharmaExpert software. The predicted cytotoxic activity of the dithiocarbamate derivatives of 9,10-anthracenedione was evaluated in vitro on cancer cells of the human lung (A549), prostate (PC3), colon (HT29) and human breast (MCF7) using the sulforhodamine B (SRB) cell viability assay. Among these compounds, 9,10-dioxo-9,10-dihydroanthracen-1-yl pyrrolidin-1-carbodithioate and 9,10-dioxo-9,10-dihydroanthracen-2-yl pyrrolidin-1-carbodithioate were identified as the most potent anticancer agents with cytotoxic activity against the MCF-7 human breast cell line with GI50 values of 1...
May 19, 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/28522265/screening-for-bioactive-natural-products-from-a-67-compound-library-of-glycyrrhiza-inflata
#3
Yan Lin, Yi Kuang, Kai Li, Shuang Wang, Wei Song, Xue Qiao, Gulnar Sabir, Min Ye
Licorice shows a variety of pharmacological activities. This work aims to discover bioactive natural products from one botanical source of licorice, Glycyrrhiza inflata. A total of 67 free phenolics were isolated to form a compound library. Based on the bioactivities of licorice, these compounds were screened using cell- or enzyme-based bioassay methods. A total of 11 compounds exhibited potent cytotoxic activities against three human cancer cell lines (HepG2, SW480 and MCF7), while showed little toxicity on human normal cell lines LO2 and HEK293T...
May 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28518146/acyl-coa-thioesterase-7-is-involved-in-cell-cycle-progression-via-regulation-of-pkc%C3%AE-p53-p21-signaling-pathway
#4
Seung Hee Jung, Hyung Chul Lee, Hyun Jung Hwang, Hyun A Park, Young-Ah Moon, Bong Cho Kim, Hyeong Min Lee, Kwang Pyo Kim, Yong-Nyun Kim, Byung Lan Lee, Jae Cheol Lee, Young-Gyu Ko, Heon Joo Park, Jae-Seon Lee
Acyl-CoA thioesterase 7 (ACOT7) is a major isoform of the ACOT family that catalyzes hydrolysis of fatty acyl-CoAs to free fatty acids and CoA-SH. However, canonical and non-canonical functions of ACOT7 remain to be discovered. In this study, for the first time, ACOT7 was shown to be responsive to genotoxic stresses such as ionizing radiation (IR) and the anti-cancer drug doxorubicin in time- and dose-dependent manners. ACOT7 knockdown induced cytostasis via activation of the p53-p21 signaling pathway without a DNA damage response...
May 18, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28515673/growth-of-mcf-7-breast-cancer-cells-and-efficacy-of-anti-angiogenic-agents-in-a-hydroxyethyl-chitosan-glycidyl-methacrylate-hydrogel
#5
Hejing Wang, Junmin Qian, Yaping Zhang, Weijun Xu, Juxiang Xiao, Aili Suo
BACKGROUND: Breast cancer negatively affects women's health worldwide. The tumour microenvironment plays a critical role in tumour initiation, proliferation, and metastasis. Cancer cells are traditionally grown in two-dimensional (2D) cultures as monolayers on a flat solid surface lacking cell-cell and cell-matrix interactions. These experimental conditions deviate from the clinical situation. Improved experimental systems that can mimic the in vivo situation are required to discover new therapies, particularly for anti-angiogenic agents that mainly target intercellular factors and play an essential role in treating some cancers...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28514506/human-adipose-derived-mesenchymal-stem-cell-secreted-cxcl1-and-cxcl8-facilitate-breast-tumor-growth-by-promoting-angiogenesis
#6
Yuan Wang, Junli Liu, Qingyuan Jiang, Jie Deng, Fen Xu, Xiaolei Chen, Fuyi Cheng, Yujing Zhang, Yunqi Yao, Zhemin Xia, Xia Xu, Xiaolan Su, Meijuan Huang, Lei Dai, Yang Yang, Shuang Zhang, Dechao Yu, Robert Chunhua Zhao, Yuquan Wei, Hongxin Deng
Autologous adipose tissue or adipose tissue with additive adipose-derived mesenchymal stem cells (ADSCs) is used in the breast reconstruction of breast cancer patients who undergo mastectomy. ADSCs play an important role in the angiogenesis and adipogenesis, which make it much better than other materials. However, ADSCs may promote residual tumor cells to proliferate or metastasize, and the mechanism is still not fully understood. In our present study, we demonstrated that hADSCs could facilitate tumor cells growth after co-injection with MCF7 and ZR-75-30 breast cancer cells (BCCs) by promoting angiogenesis, but hADSCs showed limited effect on the growth of MDA-MB-231 BCCs...
May 17, 2017: Stem Cells
https://www.readbyqxmd.com/read/28512032/cytotoxic-triterpene-diglycosides-from-the-sea-cucumber-stichopus-horrens
#7
Nguyen Xuan Cuong, Le Thi Vien, Le Hoang, Tran Thi Hong Hanh, Do Thi Thao, Nguyen Van Thanh, Nguyen Hoai Nam, Do Cong Thung, Phan Van Kiem, Chau Van Minh
Using various chromatographic separation techniques, eight triterpene diglycosides (1-8), including four new compounds namely stichorrenosides A-D (1-4), were isolated from a methanol extract of the Vietnamese sea cucumber S. horrens. Their structures were elucidated based on spectroscopic analyses, including HR ESI MS, 1D and 2D NMR. Their in vitro cytotoxic activity against five human cancer cell lines, Hep-G2 (hepatoma cancer), KB (epidermoid carcinoma), LNCaP (prostate cancer), MCF7 (breast cancer), and SK-Mel2 (melanoma), was evaluated using SRB methods...
May 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28511566/polar-steroid-derivatives-from-the-vietnamese-starfish-astropecten-polyacanthus
#8
Le Thi Vien, Tran Thi Hong Hanh, Pham Thi Hong, Nguyen Van Thanh, Tran Thu Huong, Nguyen Xuan Cuong, Nguyen Hoai Nam, Do Cong Thung, Phan Van Kiem, Chau Van Minh
Five polar steroid derivatives, including one new glycosylated polyhydroxysteroid namely polyacanthoside A (1), were isolated from the water-soluble materials from the MeOH extract of the Vietnamese starfish Astropecten polyacanthus using various chromatographic separations. The structure elucidation was confirmed by spectroscopic experiments such as HR-ESI-MS, 1D and 2D NMR. Among the isolated compounds, (20R,24S)-3β,6α,8,15β,24-pentahydroxy-5α-cholestane (3) showed significant cytotoxic effect against five human cancer cell lines as HepG2, KB, LNCaP, MCF7 and SK-Mel2 with the IC50 values from 18...
May 16, 2017: Natural Product Research
https://www.readbyqxmd.com/read/28507950/preparation-and-characterization-of-pistacia-khinjuk-gum-nanoparticles-using-response-surface-method-evaluation-of-its-anti-bacterial-performance-and-cytotoxicity
#9
Ali Fattahi, Tahereh Sakvand, Marziyeh Hajialyani, Behzad Shahbazi, Mohammad Shakiba, Ahmad Tajehmiri, Ebrahim Shakiba
Purpose: This study aims to prepare a novel, natural nanoparticle (NP) as a drug carrier, which also has inherent therapeutic effects. Methods: Pistacia khinjuk gum NPs were prepared and Response surface methodology (RSM) was used for statistical analysis of data and optimizing the size of NPs. Results: NPs were in the range of 75.85-241.3 nm. The optimization study was carried out, and an optimized size (70.86nm) was obtained using DMSO as a solvent. The volume of the organic phase was 111.25µl, and the concentration of gum was 1% w/v...
April 2017: Advanced Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28507941/in-vitro-cytotoxicity-effects-of-197-au-pamamg4-and-198-au-pamamg4-nanocomposites-against-mcf7-and-4t1-breast-cancer-cell-lines
#10
Simin Janitabar-Darzi, Reza Rezaei, Kamal Yavari
Purpose: Study on gold based therapeutic agents for cancer cells deracination has become under scrutiny in recent years owing to effective treatments are not available for rapidly progressive cancers. The aim of present study was to examine efficiency of radioactive (198)Au/PAMAMG4 and non-radioactive (197)Au/PAMAMG4 nancomposites against 4T1 and MCF7 breast cancer cell lines. Methods: The PAMAMG4 dendrimer was treated with the gold anions and then, the mixture was chemically reduced by NaBH4. Prepared (197)Au/PAMAMG4 was bombarded by thermal neutrons in the Tehran Research Reactor to (198)Au/PAMAMG4 be produced...
April 2017: Advanced Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28507436/design-of-polyaspartic-acid-peptide-poly-ethylene-glycol-poly-%C3%AE%C2%B5-caprolactone-nanoparticles-as-a-carrier-of-hydrophobic-drugs-targeting-cancer-metastasized-to-bone
#11
Jinsong Liu, Youyun Zeng, Shuai Shi, Lihua Xu, Hualin Zhang, Janak L Pathak, Yihuai Pan
Treatment of cancer metastasized to bone is still a challenge due to hydrophobicity, instability, and lack of target specificity of anticancer drugs. Poly (ethylene glycol)-poly (ε-caprolactone) polymer (PEG-PCL) is an effective, biodegradable, and biocompatible hydrophobic drug carrier, but lacks bone specificity. Polyaspartic acid with eight peptide sequences, that is, (Asp)8, has a strong affinity to bone surface. The aim of this study was to synthesize (Asp)8-PEG-PCL nanoparticles as a bone-specific carrier of hydrophobic drugs to treat cancer metastasized to bone...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28501600/development-of-a-human-epidermal-growth-factor-derivative-with-egfr-blocking-and-depleted-biological-activities-a-comparative-in-vitro-study-using-egfr-positive-breast-cancer-cells
#12
Masomeh Mehrabi, Kamran Mansouri, Bijan Solymani, Zohreh Hossein-Khani, Mohsen Shahlaie, Reza Khodarahmi
Epidermal growth factor (EGF) is a local growth factor that stimulates cell growth, proliferation, and differentiation by binding to its receptor EGFR. EGF and EGFR are involved in many aspects of the development of carcinomas. Because EGFR has been found to be over-expressed in many tumors of epithelial origin, it is a potential target for antitumor therapy. In this study we designed a mutated form of hEGF (mEGF) with a deletion of four amino acids residues (Gln(43), Tyr(44), Arg(45) and Asp(46)) in order to show importance of Leu spatial location for EGFR binding/activation...
May 10, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28499350/transcription-factor-associated-combinatorial-epigenetic-pattern-reveals-higher-transcriptional-activity-of-tcf7l2-regulated-intragenic-enhancers
#13
Qi Liu, Russell Bonneville, Tianbao Li, Victor X Jin
BACKGROUND: Recent studies have suggested that combinations of multiple epigenetic modifications are essential for controlling gene expression. Despite numerous computational approaches have been developed to decipher the combinatorial epigenetic patterns or "epigenetic code", none of them has explicitly addressed the relationship between a specific transcription factor (TF) and the patterns. METHODS: Here, we developed a novel computational method, T-cep, for annotating chromatin states associated with a specific TF...
May 12, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28495622/a-new-l-amino-acid-oxidase-from-bothrops-jararacussu-snake-venom-isolation-partial-characterization-and-assessment-of-pro-apoptotic-and-antiprotozoal-activities
#14
Sante E I Carone, Tássia R Costa, Sandra M Burin, Adélia C O Cintra, Karina F Zoccal, Francine J Bianchini, Luiz F F Tucci, João J Franco, Maria R Torqueti, Lúcia H Faccioli, Sérgio de Albuquerque, Fabíola A de Castro, Suely V Sampaio
A new l-amino acid oxidase (LAAO) from Bothrops jararacussu venom (BjussuLAAO-II) was isolated by using a three-step chromatographic procedure based on molecular exclusion, hydrophobicity, and affinity. BjussuLAAO-II is an acidic enzyme with pI=3.9 and molecular mass=60.36kDa that represents 0.3% of the venom proteins and exhibits high enzymatic activity (4884.53U/mg/mim). We determined part of the primary sequence of BjussuLAAO-II by identifying 96 amino acids, from which 34 compose the N-terminal of the enzyme (ADDRNPLEECFRETDYEEFLEIARNGLSDTDNPK)...
May 8, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28494188/depletion-of-signal-recognition-particle-72kda-increases-radiosensitivity
#15
Remko Prevo, Gaganpreet S Tiwana, Timothy S Maughan, Francesca M Buffa, W Gillies McKenna, Geoff S Higgins
The identification of genetic determinants that underpin tumor radioresistance can help the development of targeted radiosensitizers or aid personalization of radiotherapy treatment. Here we identify signal recognition particle 72 kDa (SRP72) as a novel gene involved in radioresistance. Knockdown of SRP72 resulted in significant radiosensitization of HeLa (cervical), PSN-1 (pancreatic), and T24 (bladder), BT-549 (breast) and MCF7 (breast) tumor lines as measured by colony formation assays. SRP72 depletion also resulted in the radiosensitization of normal lung fibroblast cell lines (HFL1 and MRC-5), demonstrating that the effect is not restricted to tumor cells...
May 11, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28476032/activation-of-akt-characterizes-estrogen-receptor-positive-human-breast-cancers-which-respond-to-anthracyclines
#16
Synnøve Yndestad, Eilin Austreid, Ida R Svanberg, Stian Knappskog, Per E Lønning, Hans P Eikesdal
Anthracyclines are key components of human breast cancer chemotherapy. Here, we explored the role of Akt signaling in anthracycline resistance.The antitumor activity of doxorubicin and Akt inhibitor A-443654 alone or combined was examined in estrogen receptor (ER) positive and negative human breast cancer cell lines. Further, we examined mRNA changes induced by anthracyclines in locally advanced breast cancers biopsied before and after treatment in two clinical trials.Doxorubicin increased Akt phosphorylation in ER positive MCF7 and T47D cell lines, with no effect in ER negative MDA-MB231 breast cancer cells...
April 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28472723/activity-of-phosphatase-sensitive-5-aminolevulinic-acid-prodrugs-in-cancer-cell-lines
#17
Viktorija Herceg, Norbert Lange, Eric Allémann, Andrej Babič
5-aminolevulinc acid (5-ALA)-based photodynamic therapy (PDT) and photodiagnosis (PD) present many advantages over treatments with conventional photosensitizers (PS). It offers great tumor specificity, reduced photosensitivity reactions caused by PS accumulation in non-targeted tissues and also inherent PS metabolism into endogenous non-fluorescent heme. However, chemical instability, low bioavailability and poor pharmacokinetic profile limit systemic efficacy of 5-ALA. Here, we present a comprehensive in vitro evaluation of novel phosphatase-sensitive prodrugs of 5-ALA...
April 26, 2017: Journal of Photochemistry and Photobiology. B, Biology
https://www.readbyqxmd.com/read/28468958/an-immediate-late-gene-expression-module-decodes-erk-signal-duration
#18
Florian Uhlitz, Anja Sieber, Emanuel Wyler, Raphaela Fritsche-Guenther, Johannes Meisig, Markus Landthaler, Bertram Klinger, Nils Blüthgen
The RAF-MEK-ERK signalling pathway controls fundamental, often opposing cellular processes such as proliferation and apoptosis. Signal duration has been identified to play a decisive role in these cell fate decisions. However, it remains unclear how the different early and late responding gene expression modules can discriminate short and long signals. We obtained both protein phosphorylation and gene expression time course data from HEK293 cells carrying an inducible construct of the proto-oncogene RAF By mathematical modelling, we identified a new gene expression module of immediate-late genes (ILGs) distinct in gene expression dynamics and function...
May 3, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28467796/dickkopf-related-protein-2-induces-g0-g1-arrest-and-apoptosis-through-suppressing-wnt-%C3%AE-catenin-signaling-and-is-frequently-methylated-in-breast-cancer
#19
Junhao Mu, Tianli Hui, Bianfei Shao, Lili Li, Zhenfang Du, Li Lu, Lin Ye, Shuman Li, Qianqian Li, Qian Xiao, Zhu Qiu, Yan Zhang, Jiangxia Fan, Guosheng Ren, Qian Tao, Tingxiu Xiang
Dickkopf-related protein 2 (DKK2) is one of the antagonists of Wnt/β-catenin signaling, with its downregulation reported in multiple cancers. However, how DKK2 contributes to breast tumorigenesis remains unclear. We examined its expression and promoter methylation in 10 breast tumor cell lines, 98 primary tumors, and 21 normal breast tissues. Compared with normal tissues, DKK2 was frequently silenced in breast cell lines (7/8). DKK2 promoter methylation was detected in 77.8% of cell lines and 86.7% of breast tumors; while rarely detected in normal breast tissues (19%), indicating common DKK2 methylation in breast cancer...
April 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28467092/metabolomics-proteomics-combined-approach-identifies-differential-metabolism-associated-molecular-events-between-senescence-and-apoptosis
#20
Mengqiu Wu, Hui Ye, Chang Shao, Xiao Zheng, Qingran Li, Lin Wang, Min Zhao, Gaoyuan Lu, Baoqiang Chen, Jun Zhang, Yun Wang, Guangji Wang, Haiping Hao
Apoptosis and senescence are two types of cell fates in response to chemotherapy. Besides canonical pathways that mediate cell fates, cancer cell metabolism has been revealed as a crucial factor affecting cell fate decisions and thus represents a new target for antitumor therapy. Therefore, a comprehensive description of metabolic pathways underlying cell senescence and apoptosis in response to chemotherapy is highly demanded for therapeutic exploitation of both processes. Herein we employed a metabolomics-proteomics combined approach to identify metabolism-associated molecular events that mediate cellular responses to senescence and apoptosis using doxorubicin-treated human breast cancer cells MCF7 as models...
May 10, 2017: Journal of Proteome Research
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