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https://www.readbyqxmd.com/read/27919961/effects-of-spiro-bisheterocycles-on-proliferation-and-apoptosis-in-human-breast-cancer-cell-lines
#1
Lamia Hamdan Ramdani, Oualid Talhi, Nadia Taibi, Laetitia Delort, Caroline Decombat, Artur Silva, Khaldoun Bachari, Marie-Paule Vasson, Florence Caldefie-Chezet
Breast cancer is the leading cause of cancer-related death in women worldwide and a critical public health concern. Here we investigated the anticancer potential and effects of low-molecular-weight bridgehead oxygen and nitrogen-containing spiro-bisheterocycles on proliferation and apoptosis of the human breast cancer cell lines MCF-7 and MDA-MB-231. The compounds feature a hydantoin moiety attached to either diazole, isoxazole, diazepine, oxazepine or benzodiazepine via the privileged tetrahedral spiro-linkage...
December 2016: Anticancer Research
https://www.readbyqxmd.com/read/27916892/molecular-mechanisms-of-p53-deregulation-in-cancer-an-overview-in-multiple-myeloma
#2
REVIEW
Ana B Herrero, Elizabeta A Rojas, Irena Misiewicz-Krzeminska, Patryk Krzeminski, Norma C Gutiérrez
The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 negative regulators, such as murine double minute 2 (MDM2) or murine double minute 4 (MDM4), epigenetic deregulation, or even alterations in TP53 mRNA splicing. In this work, we will review the different mechanisms of p53 pathway inhibition in cancer with special focus on multiple myeloma (MM), the second most common hematological malignancy, with low incidence of p53 mutations/deletions but growing evidence of indirect p53 pathway deregulation...
November 30, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27912078/mouse-double-minute-2-homolog-actively-suppresses-p53-activity-in-oocytes-during-mouse-folliculogenesis
#3
Chen-Xi Zhang, Qin Zhang, Yin-Yin Xie, Xue-Yan He, Cong Xiang, Xiao-Shuang Hou, Ying Zhou, Lai Chen, Guo-Xin Zhang, Geng Liu
The p53 signaling network is indispensible in cellular stress responses and tumor suppression. Negative regulations of p53 by mouse double minute 2 and 4 homologs (MDM2) and (MDM4) are an integrated component of the network and have been implicated in regulating the stress responses and the maintenance of normal development and homeostasis of multiple somatic cell lineages. However, the regulatory role of MDM2 on p53 and stress responses in female germ cells remains undetermined. Here, we used the Cre-loxP system to delete Mdm2 in oocytes at different stages of folliculogenesis in mice...
November 29, 2016: American Journal of Pathology
https://www.readbyqxmd.com/read/27911838/antagonists-of-growth-hormone-releasing-hormone-receptor-induce-apoptosis-specifically-in-retinoblastoma-cells
#4
Wai Kit Chu, Ka Sin Law, Sun On Chan, Jason Cheuk Sing Yam, Li Jia Chen, Hao Zhang, Herman S Cheung, Norman L Block, Andrew V Schally, Chi Pui Pang
Retinoblastoma (RB) is the most common intraocular cancer in children worldwide. Current treatments mainly involve combinations of chemotherapies, cryotherapies, and laser-based therapies. Severe or late-stage disease may require enucleation or lead to fatality. Recently, RB has been shown to arise from cone precursor cells, which have high MDM2 levels to suppress p53-mediated apoptosis. This finding leads to the hypothesis that restoring apoptosis mechanisms in RBs could specifically kill the cancer cells without affecting other retinal cells...
November 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27908926/the-evolution-of-the-ribosomal-protein-mdm2-p53-pathway
#5
Chad Deisenroth, Derek A Franklin, Yanping Zhang
The progression of our understanding of ribosomal proteins as static building blocks of the ribosome to highly integrated sensors of p53 surveillance and function has achieved a tremendous rate of growth over the past several decades. As the workhorse of the cell, ribosomes are responsible for translating the genetic code into the functional units that drive cell growth and proliferation. The seminal identification of ribosomal protein binding to MDM2, the negative regulator of p53, has evolved into a paradigm for ribosomal protein-MDM2-p53 signaling that extends into processes as diverse as energy metabolism to proliferation...
December 1, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27907876/rational-design-and-synthesis-of-1-5-disubstituted-tetrazoles-as-potent-inhibitors-of-the-mdm2-p53-interaction
#6
Ewa Surmiak, Constantinos G Neochoritis, Bogdan Musielak, Aleksandra Twarda-Clapa, Katarzyna Kurpiewska, Grzegorz Dubin, Carlos Camacho, Tad A Holak, Alexander Dömling
Using the computational pharmacophore-based ANCHOR.QUERY platform a new scaffold was discovered. Potent compounds evolved inhibiting the protein-protein interaction p53-MDM2. An extensive SAR study was performed based on our four-point pharmacophore model, yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using both fluorescence polarization (FP) assay and 2D-NMR-HSQC experiments.
November 16, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27906699/reversal-effects-of-local-anesthetics-on-p-glycoprotein-mediated-cancer-multidrug-resistance
#7
Yong Hu, Xiaobing Qin, Haixia Cao, Shaorong Yu, Jifeng Feng
The existence of multidrug resistance (MDR) is the main reason for failure in cancer chemotherapy. The main mechanism of MDR is the overexpression of P-glycoprotein (P-gp). P-gp, a 170 kDa transmembrane phosphorylated glycoprotein encoded by ABCB1 belonging to a member of the ATP-binding cassette (ABC) super-family of the membrane transporters, is also known as the MDR protein. Local anesthetics (LAs) are a major contributor to medical practice. As a cornerstone of analgesia, LAs provides myriad benefits...
November 30, 2016: Anti-cancer Drugs
https://www.readbyqxmd.com/read/27905468/protein-peptide-molecular-docking-with-large-scale-conformational-changes-the-p53-mdm2-interaction
#8
Maciej Pawel Ciemny, Aleksander Debinski, Marta Paczkowska, Andrzej Kolinski, Mateusz Kurcinski, Sebastian Kmiecik
Protein-peptide interactions are often associated with large-scale conformational changes that are difficult to study either by classical molecular modeling or by experiment. Recently, we have developed the CABS-dock method for flexible protein-peptide docking that enables large-scale rearrangements of the protein chain. In this study, we use CABS-dock to investigate the binding of the p53-MDM2 complex, an element of the cell cycle regulation system crucial for anti-cancer drug design. Experimental data suggest that p53-MDM2 binding is affected by significant rearrangements of a lid region - the N-terminal highly flexible MDM2 fragment; however, the details are not clear...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27903487/disturbed-p53-mdm2-feedback-loop-contributes-to-thoracic-aortic-dissection-formation-and-may-be-a-result-of-trim-25-overexpression
#9
Bin Gong, Zhiwei Wang, Min Zhang, Zhipeng Hu, Zongli Ren, Zheng Tang, Wanli Jiang, Lianghao Cheng, Jun Huang, Wei Ren, Qingtao Wang
BACKGROUND: The development of thoracic aortic dissection (TAD) is attributed to a broad range of degenerative, genetic, structural, oxidative, apoptotic, and acquired disease states. In this study, we examined the role of the disturbed p53-MDM2 feed-back loop in the formation of TAD, and one of a potential feed-back loop regulator, TRIM-25. METHODS: Surgical specimens of the aorta from TAD patients (n=10) and controls (n=10) were tested for α-smooth muscle actin (α-SMA),p53,murine double minute2(MDM2) and tripartite motif protein-25(TRIM-25) by western blot, immunohistochemical staining and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) , respectively...
November 26, 2016: Annals of Vascular Surgery
https://www.readbyqxmd.com/read/27897991/the-double-role-of-p53-in-cancer-and-autoimmunity-and-its-potential-as-therapeutic-target
#10
REVIEW
Alessandra Fierabracci, Marsha Pellegrino
p53 is a sequence-specific short-lived transcription factor expressed at low concentrations in various tissues while it is upregulated in damaged, tumoral or inflamed tissue. In normally proliferating cells, p53 protein levels and function are tightly controlled by main regulators, i.e., MDM2 (mouse double minute 2) and MDM4 proteins. p53 plays an important role due to its ability to mediate tumor suppression. In addition to its importance as a tumor suppressor, p53 coordinates diverse cellular responses to stress and damage and plays an emerging role in various physiological processes, including fertility, cell metabolism, mitochondrial respiration, autophagy, cell adhesion, stem cell maintenance and development...
November 25, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27894957/dna-methylation-profiling-identifies-ptrf-cavin-1-as-a-novel-tumor-suppressor-in-ewing-sarcoma-when-co-expressed-with-caveolin-1
#11
Juan Huertas-Martínez, Franck Court, Santiago Rello-Varona, David Herrero-Martín, Olga Almacellas-Rabaiget, Miguel Sáinz-Jaspeado, Silvia Garcia-Monclús, Laura Lagares-Tena, Raquel Buj, Lourdes Hontecillas-Prieto, Ana Sastre, Daniel Azorin, Xavier Sanjuan, Roser López-Alemany, Sebastian Moran, Josep Roma, Soledad Gallego, Jaume Mora, Xavier García Del Muro, Paloma H Giangrande, Miquel A Peinado, Javier Alonso, Enrique de Alava, Dave Monk, Manel Esteller, Oscar M Tirado
Epigenetic modifications have been shown to be important in developmental tumors as Ewing sarcoma. We profiled the DNA methylation status of 15 primary tumors, 7 cell lines, 10 healthy tissues and 4 human mesenchymal stem cells lines samples using the Infinium Human Methylation 450k. Differential methylation analysis between Ewing sarcoma and reference samples revealed 1,166 hypermethylated and 864 hypomethylated CpG sites (Bonferroni p<0.05, δ-β-value with absolute difference of >0.20) corresponding to 392 and 470 genes respectively...
November 25, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27890964/association-of-the-mdm2-snp285-polymorphism-with-cancer-susceptibility-a-meta-analysis
#12
REVIEW
Ping Wang, Meilin Wang, Sanqiang Li, Lingjun Ma, Shoumin Xi, Jing He
The mouse double minute 2 (MDM2) gene encodes a negative regulator for p53, and the polymorphism SNP285 in the promoter region of MDM2 gene has been implicated in cancer risk, but individual published studies had inconclusive results. Therefore, we performed this meta-analysis to obtain a more precise estimation between MDM2 SNP285 polymorphism and risk of cancer. A systematic literature search was performed using the PubMed, Embase, and Chinese Biomedical (CBM) databases. Ultimately, 16 published studies comprising 14,573 cases and 9,115 controls were included...
2016: Disease Markers
https://www.readbyqxmd.com/read/27888811/the-role-of-p53-in-cancer-drug-resistance-and-targeted-chemotherapy
#13
REVIEW
Karin Hientz, André Mohr, Dipita Bhakta-Guha, Thomas Efferth
Cancer has long been a grievous disease complicated by innumerable players aggravating its cure. Many clinical studies demonstrated the prognostic relevance of the tumor suppressor protein p53 for many human tumor types. Overexpression of mutated p53 with reduced or abolished function is often connected to resistance to standard medications, including cisplatin, alkylating agents (temozolomide), anthracyclines, (doxorubicin), antimetabolites (gemcitabine), antiestrogenes (tamoxifen) and EGFR-inhibitors (cetuximab)...
November 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/27886165/induction-of-tumor-apoptosis-through-a-circular-rna-enhancing-foxo3-activity
#14
William W Du, Ling Fang, Weining Yang, Nan Wu, Faryal Mehwish Awan, Zhenguo Yang, Burton B Yang
Circular RNAs are a class of non-coding RNAs that are receiving extensive attention. Despite reports showing circular RNAs acting as microRNA sponges, the biological functions of circular RNAs remain largely unknown. We show that in patient tumor samples and in a panel of cancer cells, circ-Foxo3 was minimally expressed. Interestingly, during cancer cell apoptosis, the expression of circ-Foxo3 was found to be significantly increased. We found that silencing endogenous circ-Foxo3 enhanced cell viability, whereas ectopic expression of circ-Foxo3 triggered stress-induced apoptosis and inhibited the growth of tumor xenografts...
November 25, 2016: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27885271/p53-pathway-dysfunction-is-highly-prevalent-in-acute-myeloid-leukemia-independent-of-tp53-mutational-status
#15
A Quintás-Cardama, C Hu, A Qutub, Y H Qiu, X Zhang, S Post, N Zhang, K Coombes, S M Kornblau
TP53 mutations are associated with the lowest survival rates in acute myeloid leukemia (AML). In addition to mutations, loss of p53 function can arise via aberrant expression of proteins that regulate p53 stability and function. We examined a large AML cohort using proteomics, mutational profiling, and network analyses and showed that 1) p53 stabilization is universal in mutant TP53 samples, it is frequent in samples with wild-type TP53, and in both cases portends an equally dismal prognosis; 2) the p53 negative regulator Mdm2 is frequently overexpressed in samples retaining wild-type TP53 alleles, coupled with absence of p21 expression and dismal prognosis similar to that of cases with p53 stabilization; 3) AML samples display unique patterns of p53 pathway protein expression, which segregate prognostic groups with distinct cure rates; 4) such patterns of protein activation unveil potential AML vulnerabilities that can be therapeutically exploited...
November 25, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27882940/mdm2-prevents-spontaneous-tubular-epithelial-cell-death-and-acute-kidney-injury
#16
Dana Thomasova, Martrez Ebrahim, Kristina Fleckinger, Moying Li, Jakob Molnar, Bastian Popper, Helen Liapis, Ahmed M Kotb, Florian Siegerist, Nicole Endlich, Hans-Joachim Anders
Murine double minute-2 (MDM2) is an E3-ubiquitin ligase and the main negative regulator of tumor suppressor gene p53. MDM2 has also a non-redundant function as a modulator of NF-kB signaling. As such it promotes proliferation and inflammation. MDM2 is highly expressed in the unchallenged tubular epithelial cells and we hypothesized that MDM2 is necessary for their survival and homeostasis. MDM2 knockdown by siRNA or by genetic depletion resulted in demise of tubular cells in vitro. This phenotype was completely rescued by concomitant knockdown of p53, thus suggesting p53 dependency...
November 24, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27882102/inhibition-of-antiviral-drug-cidofovir-on-proliferation-of-human-papillomavirus-infected-cervical-cancer-cells
#17
Jing Yang, Lv-Xia Dai, Ming Chen, Bei Li, Nana Ding, Gang Li, Yan-Qing Liu, Ming-Yuan Li, Bao-Ning Wang, Xin-Li Shi, Hua-Bing Tan
In order to evaluate the potential application value of cidofovir (CDV) in the prevention of human papillomavirus (HPV) infection and treatment of cervical cancer, the inhibitory effect of CDV on the proliferation of HPV 18-positive HeLa cells in cervical cancer was preliminarily investigated, using cisplatin (DDP) as a positive control. An MTT assay was used to analyze the effects of CDV and DDP on HeLa cell proliferation. In addition, clone formation assay and Giemsa staining were used to examine the extent of HeLa cell apoptosis caused by CDV and DDP...
November 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/27879515/atypical-spindle-cell-lipomatous-tumor-clinicopathologic-characterization-of-232-cases-demonstrating-a-morphologic-spectrum
#18
Adrian Mariño-Enriquez, Alessandra F Nascimento, Azra H Ligon, Cherwei Liang, Christopher D M Fletcher
The classification of atypical adipocytic neoplasms with spindle cell features remains challenging. To better define this category of low-grade lipomatous neoplasms, we present herein the clinical, histologic, and immunohistochemical characteristics of a large series of 232 atypical spindle cell lipomatous tumors. The lesions affected 140 males and 92 females, at an average age of 54 years (range, 6 to 87 y), clinically presenting as a persistent or enlarging mass with a median size of 5 cm. The anatomic distribution of the tumors was wide, predominating in the limbs and limb girdles (147 cases, 63%), mainly in the hands and feet (17% and 11%, respectively), with equal distribution between subcutaneous and deeper locations...
November 22, 2016: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/27874234/bioorthogonal-probes-for-the-study-of-mdm2-p53-inhibitors-in-cells-and-development-of-high-content-screening-assays-for-drug-discovery
#19
Pier Luca D'Alessandro, Nicole Buschmann, Markus Kaufmann, Pascal Furet, Frederic Baysang, Reto Brunner, Andreas Marzinzik, Thomas Vorherr, Therese-Marie Stachyra, Johannes Ottl, Dimitrios E Lizos, Amanda Cobos-Correa
To study the behavior of MDM2-p53 inhibitors in a disease-relevant cellular model, we have developed and validated a set of bioorthogonal probes that can be fluorescently labeled in cells and used in high-content screening assays. By using automated image analysis with single-cell resolution, we could visualize the intracellular target binding of compounds by co-localization and quantify target upregulation upon MDM2-p53 inhibition in an osteosarcoma model. Additionally, we developed a high-throughput assay to quantify target occupancy of non-tagged MDM2-p53 inhibitors by competition and to identify novel chemical matter...
November 22, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27871087/the-hdm2-mdm2-inhibitor-nvp-cgm097-inhibits-tumor-cell-proliferation-and-shows-additive-effects-with-5-fluorouracil-on-the-p53-p21-rb-e2f1-cascade-in-the-p53wildtype-neuroendocrine-tumor-cell-line-got1
#20
Clemens Reuther, Vera Heinzle, Svenja Nölting, Sabine Herterich, Stefanie Hahner, Ensar Halilovic, Sébastien Jeay, Jens U Wuerthner, Elke Tatjana Aristizabal Prada, Gerald Spöttl, Julian Maurer, Christoph J Auernhammer
No abstract text is available yet for this article.
November 21, 2016: Neuroendocrinology
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