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Ubiquitin myeloma

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https://www.readbyqxmd.com/read/29047025/targeting-the-ubiquitin-proteasome-system-for-cancer-treatment-discovering-novel-inhibitors-from-nature-and-drug-repurposing
#1
Claire L Soave, Tracey Guerin, Jinbao Liu, Q Ping Dou
In the past 15 years, the proteasome has been validated as an anti-cancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance, and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning towards the goal of discovering effective, economical, low toxicity proteasome-inhibitory anti-cancer drugs...
October 18, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29025286/-thalidomide-therapy-in-relapsed-diffuse-large-b-cell-lymphoma-in-elderly-patients-three-cases
#2
Nikolett Wohner, Gergely Varga, Péter Szloboda, Péter Farkas, András Masszi, Laura Horváth, Gergely Szombath, Judit Várkonyi, Szabolcs Benedek, Tamás Masszi
Diffuse large B-cell lymphoma (DLBCL), a high-grade lymphoproliferative disease, is the most common lymphoma in adults, representing 31% of non-Hodgkin lymphomas (NHL). In elderly patients treatment is problematic because of the high toxicity of standard chemotherapy protocols, especially in relapsed cases, where high-dose chemotherapy and haematopoietic stem cell transplantation would be the best choice. More and more data is becoming available on alternative treatment of refractory/relapsed NHL, including studies on the positive effect of thalidomide and second generation IMiDs in DLBCL, which are already part of the standard treatment protocol in myeloma multiplex and myelodysplasia...
October 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/28932850/amino-and-chloro-8-hydroxyquinolines-and-their-copper-complexes-as-proteasome-inhibitors-and-antiproliferative-agents
#3
Valentina Oliveri, Valeria Lanza, Danilo Milardi, Maurizio Viale, Irena Maric, Carmelo Sgarlata, Graziella Vecchio
Proliferation and programmed cell death are tightly correlated with the ubiquitin-proteasome system (UPS). Alterations in the UPS may be implicated in pathological conditions such as the proteasome over-activity in cancer cells. Mounting evidence indicates that many types of actively proliferating malignant cells are more sensitive to proteasome inhibition than normal cells, and therefore UPS inhibitors are actively pursued as anticancer agents. The approval of the proteasome inhibitor drug bortezomib for the treatment of myeloma and lymphoma further highlights the need for UPS inhibitors...
October 18, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28927072/arsenic-trioxide-potentiates-sensitivity-of-multiple-myeloma-cells-to-lenalidomide-by-upregulating-cereblon-expression-levels
#4
Yuan Jian, Wen Gao, Chuanying Geng, Huixing Zhou, Yun Leng, Yanchen Li, Wenming Chen
The mechanism of the anti-myeloma effect of the immunomodulatory drug lenalidomide relies upon the binding of lenalidomide or an analogue to cereblon (CRBN) ubiquitin ligase, which inhibits it and results in the degradation of Ikaros-family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). To determine whether the traditional Chinese medicine arsenic trioxide, could potentiate sensitivity of multiple myeloma (MM) cells to lenalidomide and identify the mechanism by which this happens, the present study investigated how arsenic trioxide affected CRBN on MM cell lines and examined the anti-myeloma effect and mechanism in the combination of arsenic trioxide and lenalidomide...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28911826/immunoproteasome-selective-and-non-selective-inhibitors-a-promising-approach-for-the-treatment-of-multiple-myeloma
#5
REVIEW
Roberta Ettari, Maria Zappalà, Silvana Grasso, Caterina Musolino, Vanessa Innao, Alessandro Allegra
The ubiquitin-proteasome system (UPS) is the major non-lysosomal proteolytic system for the degradation of abnormal or damaged proteins no longer required. The proteasome is involved in degradation of numerous proteins which regulate the cell cycle, indicating a role in controlling cell proliferation and maintaining cell survival. Defects in the UPS can lead to anarchic cell proliferation and to tumor development. For these reasons UPS inhibition has become a significant new strategy for drug development in cancer treatment...
September 11, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28878026/the-p97-inhibitor-cb-5083-is-a-unique-disrupter-of-protein-homeostasis-in-models-of-multiple-myeloma
#6
Ronan Le Moigne, Blake T Aftab, Stevan Djakovic, Eugen Dhimolea, Eduardo Valle, Megan Murnane, Emily M King, Ferdie Soriano, Mary-Kamala Menon, Zhi Yong Wu, Stephen T Wong, Grace J Lee, Bing Yao, Arun P Wiita, Christine Lam, Julie Rice, Jinhai Wang, Marta Chesi, P Leif Bergsagel, Marianne Kraus, Christoph Driessen, Szerenke Kiss von Soly, F Michael Yakes, David Wustrow, Laura Shawver, Han-Jie Zhou, Thomas G Martin, Jeffrey L Wolf, Constantine S Mitsiades, Daniel J Anderson, Mark Rolfe
Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system (UPS) and CB-5083, a first in class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematological and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma (MM) cell lines and a number of in vivo MM models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response (UPR) and apoptosis...
September 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28874810/innate-immune-activating-ligand-sumoylation-affects-tumor-cell-recognition-by-nk-cells
#7
Beatrice Zitti, Rosa Molfetta, Cinzia Fionda, Linda Quatrini, Helena Stabile, Mario Lecce, Valeria de Turris, Maria Rosaria Ricciardi, Maria Teresa Petrucci, Marco Cippitelli, Angela Gismondi, Angela Santoni, Rossella Paolini
Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28673317/the-ubiquitin-conjugating-enzyme-ube2o-modulates-c-maf-stability-and-induces-myeloma-cell-apoptosis
#8
Yujia Xu, Zubin Zhang, Jie Li, Jiefei Tong, Biyin Cao, Paul Taylor, Xiaowen Tang, Depei Wu, Michael F Moran, Yuanying Zeng, Xinliang Mao
BACKGROUND: UBE2O is proposed as a ubiquitin-conjugating enzyme, but its function was largely unknown. METHODS: Mass spectrometry was applied to identify c-Maf ubiquitination-associated proteins. Immunoprecipitation was applied for c-Maf and UBE2O interaction. Immunoblotting was used for Maf protein stability. Luciferase assay was used for c-Maf transcriptional activity. Lentiviral infections were applied for UBE2O function in multiple myeloma (MM) cells. Flow cytometry and nude mice xenografts were applied for MM cell apoptosis and tumor growth assay, respectively...
July 3, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28657369/naphthoquinone-amino-acid-derivatives-synthesis-and-biological-activity-as-proteasome-inhibitors
#9
Mauro Marastoni, Claudio Trapella, Alessandra Scotti, Anna Fantinati, Valeria Ferretti, Erika Marzola, Gallerani Eleonora, Riccardo Gavioli, Delia Preti
The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division. Because of their antitumour activity, different classes of proteasome inhibitors have been identified to date. Some of these compounds are currently employed in the clinical treatment of several types of cancer among which multiple myeloma. Here, we describe the design, chemistry, biological activity and modelling studies of a large series of amino acid derivatives linked to a naphthoquinone pharmacophoric group through variable spacers...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28653881/effects-of-dtx3l-on-the-cell-proliferation-adhesion-and-drug-resistance-of-multiple-myeloma-cells
#10
Yaodong Shen, Yuxiang Sun, Linlin Zhang, Hong Liu
Cell adhesion-mediated drug resistance is an important factor that influences the effects of chemotherapy in multiple myeloma. DTX3L, a ubiquitin ligase, plays a key role in cell-cycle-related process. Here, we found that the expression of DTX3L gradually increased during the proliferation of myeloma cells, which resulted in arrest of the cell cycle in the G1 phase and promoted the adherence of myeloma cells to fibronectin or bone marrow stromal cells. In addition, silencing of DTX3L improved sensitivity to chemotherapy drugs in multiple myeloma cell lines adherent to bone marrow stromal cells and increased the expression of caspase-3 and poly-adenosine diphosphate-ribose polymerase, two markers of apoptosis...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28599191/targeting-autophagy-in-multiple-myeloma
#11
REVIEW
Zhuang Yun, Jin Zhichao, Yao Hao, Ji Ou, Yang Ran, Dong Wen, Shen Qun
Autophagy plays an important role in plasma cell ontogeny and in the pathophysiology of multiple myeloma. Autophagy is usually considered a pro-survival mechanism, and cooperates with the ubiquitin proteasome system in maintaining the homeostasis of myeloma cells by degrading excessive and misfolded proteins for energy recycling. Therefore, the inhibition of autophagy could effectively induce death in myeloma cells, and could synergize with proteasome inhibitors. However, the excessive activation of autophagy could also lead to the extreme degradation of the organelles that induce autophagic cell death...
August 2017: Leukemia Research
https://www.readbyqxmd.com/read/28530236/psilac-mass-spectrometry-reveals-zfp91-as-imid-dependent-substrate-of-the-crl4-crbn-ubiquitin-ligase
#12
Jian An, Charles M Ponthier, Ragna Sack, Jan Seebacher, Michael B Stadler, Katherine A Donovan, Eric S Fischer
Thalidomide and its derivatives lenalidomide and pomalidomide (IMiDs) are effective treatments of haematologic malignancies. It was shown that IMiDs impart gain-of-function properties to the CUL4-RBX1-DDB1-CRBN (CRL4(CRBN)) ubiquitin ligase that enable binding, ubiquitination and degradation of key therapeutic targets such as IKZF1, IKZF3 and CSNK1A1. While these substrates have been implicated as efficacy targets in multiple myeloma (MM) and 5q deletion associated myelodysplastic syndrome (del(5q)-MDS), other targets likely exist...
May 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/28495797/ixazomib-enhances-parathyroid-hormone-induced-%C3%AE-catenin-t-cell-factor-signaling-by-dissociating-%C3%AE-catenin-from-the-parathyroid-hormone-receptor
#13
Yanmei Yang, Hong Lei, Ya-Wei Qiang, Bin Wang
The anabolic action of PTH in bone is mostly mediated by cAMP/PKA and Wnt-independent activation of β-catenin/T-cell factor (TCF) signaling. β-Catenin switches the PTH receptor (PTHR) signaling from cAMP/PKA to PLC/PKC activation by binding to the PTHR. Ixazomib (Izb) was recently approved as the first orally administered proteasome inhibitor for the treatment of multiple myeloma; it acts in part by inhibition of pathological bone destruction. Proteasome inhibitors were reported to stabilize β-catenin by the ubiquitin-proteasome pathway...
July 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28441582/synthesis-and-antiproteasomal-activity-of-novel-o-benzyl-salicylamide-based-inhibitors-built-from-leucine-and-phenylalanine
#14
Radek Jorda, Jan Dušek, Eva Řezníčková, Karel Pauk, Pratibha P Magar, Aleš Imramovský, Vladimír Kryštof
Inhibition of protein degradation is one of strategies for suppression of uncontrolled proliferation of cancer cells. Proteolytic degradation in cells is mainly ensured by proteasome and its inhibition by bortezomib showed benefit in clinical use for the treatment of multiple myeloma. We report here the library of antiproteasomal O-benzyl salicylamides built from leucine and phenylalanine. Prepared compounds displayed antiproliferative activity on K562, CEM and U266 cancer cell lines, ranging from high micromolar to submicromolar GI50 values...
July 28, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28437394/selective-degradation-of-splicing-factor-caper%C3%AE-by-anticancer-sulfonamides
#15
Taisuke Uehara, Yukinori Minoshima, Koji Sagane, Naoko Hata Sugi, Kaoru Ogawa Mitsuhashi, Noboru Yamamoto, Hiroshi Kamiyama, Kentaro Takahashi, Yoshihiko Kotake, Mai Uesugi, Akira Yokoi, Atsushi Inoue, Taku Yoshida, Miyuki Mabuchi, Akito Tanaka, Takashi Owa
Target-protein degradation is an emerging field in drug discovery and development. In particular, the substrate-receptor proteins of the cullin-ubiquitin ligase system play a key role in selective protein degradation, which is an essential component of the anti-myeloma activity of immunomodulatory drugs (IMiDs), such as lenalidomide. Here, we demonstrate that a series of anticancer sulfonamides NSC 719239 (E7820), indisulam, and NSC 339004 (chloroquinoxaline sulfonamide, CQS) induce proteasomal degradation of the U2AF-related splicing factor coactivator of activating protein-1 and estrogen receptors (CAPERα) via CRL4(DCAF15) mediated ubiquitination in human cancer cell lines...
June 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28425720/a-cereblon-modulator-cc-220-with-improved-degradation-of-ikaros-and-aiolos
#16
Mary E Matyskiela, Weihong Zhang, Hon-Wah Man, George Muller, Godrej Khambatta, Frans Baculi, Matthew Hickman, Laurie LeBrun, Barbra Pagarigan, Gilles Carmel, Chin-Chun Lu, Gang Lu, Mariko Riley, Yoshitaka Satoh, Peter Schafer, Thomas O Daniel, James Carmichael, Brian E Cathers, Philip P Chamberlain
The drugs lenalidomide and pomalidomide bind to the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation. Here we describe CC-220 (compound 6), a cereblon modulator in clinical development for systemic lupus erythematosis and relapsed/refractory multiple myeloma. Compound 6 binds cereblon with a higher affinity than lenalidomide or pomalidomide. Consistent with this, the cellular degradation of Ikaros and Aiolos is more potent and the extent of substrate depletion is greater...
April 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28393136/development-of-%C3%AE-hairpin-peptides-for-the-measurement-of-scf-family-e3-ligase-activity-in-vitro-via-ornithine-ubiquitination
#17
Kaiulani M Houston, Adam T Melvin, Gregery S Woss, Effrat L Fayer, Marcey L Waters, Nancy L Allbritton
Regulation of the ubiquitin-proteasome system (UPS) to treat select types of cancer has become a popular area of drug discovery research. The FDA approval of proteasome inhibitors Bortezomib and Carfilzomib in the treatment of multiple myeloma has led to an increased need for chemical reporters capable of detecting and quantifying protein ubiquitination and the activity of members of the UPS including E3 ubiquitin ligases and the proteasome in the tumor cells of the patients. One limitation of peptide-based reporters is their rapid degradation in the cellular environment by cytosolic peptidases...
March 31, 2017: ACS Omega
https://www.readbyqxmd.com/read/28301380/nitroxoline-shows-antimyeloma-activity-by-targeting-the-trim25-p53-axle
#18
Hongwu Mao, Yanyun Du, Zubin Zhang, Biyin Cao, Jun Zhao, Haibin Zhou, Xinliang Mao
The aim of this study was to identify the most potent quinoline-based anti-infectives for the treatment of multiple myeloma (MM) and to understand the molecular mechanisms. A small-scale screen against a panel of marketed quinoline-based drugs was performed in MM cell lines. Cell apoptosis was examined by flow cytometry. Anti-MM activity was also evaluated in nude mice. Western blotting was performed to investigate mechanisms. Nitroxoline (NXQ) was the most effective in suppressing MM cell proliferation. NXQ induced more than 40% MM cell apoptosis within 24 h and potentiated anti-MM activities of current major drugs including doxorubicin and lenalidomide...
April 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28295550/lncrna-malat-1-elevates-hmgb1-to-promote-autophagy-resulting-in-inhibition-of-tumor-cell-apoptosis-in-multiple-myeloma
#19
Da Gao, Ai-E Lv, Hui-Ping Li, Dong-Hai Han, Ya-Peng Zhang
Long non-coding RNAs (lncRNAs) can participate in the pathological process of multiple myeloma (MM) via regulation of specific gene expression and function. This research aimed to study the role of MALAT-1 and the underlying mechanism in MM. In this study, the expression of MALAT-1 and HMGB1 protein in the bone marrow mononuclear cells from MM patients at different stages and in MM cell lines was determined by qRT-PCR and western blot, respectively. The endogenous expression of MALAT-1 and HMGB1 was modulated using lentivirus vectors transfection...
October 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28270494/blockade-of-deubiquitylating-enzyme-usp1-inhibits-dna-repair-and-triggers-apoptosis-in-multiple-myeloma-cells
#20
Deepika Sharma Das, Abhishek Das, Arghya Ray, Yan Song, Mehmet Kemal Samur, Nikhil C Munshi, Dharminder Chauhan, Kenneth C Anderson
Purpose: The ubiquitin proteasome pathway is a validated therapeutic target in multiple myeloma. Deubiquitylating enzyme USP1 participates in DNA damage response and cellular differentiation pathways. To date, the role of USP1 in multiple myeloma biology is not defined. In the present study, we investigated the functional significance of USP1 in multiple myeloma using genetic and biochemical approaches.Experimental Design: To investigate the role of USP1 in myeloma, we utilized USP1 inhibitor SJB3-019A (SJB) for studies in myeloma cell lines and patient multiple myeloma cells...
August 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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