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https://www.readbyqxmd.com/read/27917682/the-preclinical-discovery-and-development-of-bortezomib-for-the-treatment-of-mantle-cell-lymphoma
#1
Richard Arkwright, Tri Minh Pham, Jeffrey A Zonder, Q Ping Dou
Introduction- Mantle cell lymphoma (MCL) is an incurable, often aggressive B-cell malignancy. Bortezomib (BTZ), the 20S proteasome inhibitor was originally developed and approved for treatment of relapsed refractory multiple myeloma, and subsequently approved for treatment of MCL. BTZ's single-agent activity induces clinical responses in approximately one-third of relapsed MCL patients. BTZ-containing combination therapies have further improved the quality and duration of clinical responses compared to standard chemotherapies in previously untreated MCL patients...
December 3, 2016: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/27903750/nuclear-export-of-ubiquitinated-proteins-determines-the-sensitivity-of-colorectal-cancer-to-proteasome-inhibitor
#2
Tingyu Wu, Wei Chen, Yongwang Zhong, Xiaodan Hou, Shengyun Fang, Chen-Ying Liu, Guanghui Wang, Tong Yu, Yu-Yang Huang, Xuesong Ouyang, Henry Q X Li, Long Cui, Yili Yang
Although proteasome inhibitors such as Bortezomib had significant therapeutic effects in multiple myeloma and mantel cell lymphoma, they exhibited minimal clinical activity as a mono-therapy for solid tumors, including colorectal cancer. We found in the present study that proteasome inhibition induced a remarkable nuclear exportation of ubiquitinated proteins. Inhibition of CRM1, the nuclear export carrier protein, hampered protein export and synergistically enhanced the cytotoxic action of Bortezomib on colon cancer cells containing wild type p53, which underwent G2/M cell cycle block and apoptosis...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27822062/dysfunction-of-microrna-32-regulates-ubiquitin-ligase-fbxw7-in-multiple-myeloma-disease
#3
Jingsheng Hua, Tianling Ding, Linjun Yang
Dysfunction of microRNA (miRNA) expression has been associated with tumor occurrence, progression, and development. The aim of this work was to study the dysfunction of miR-32 - an miRNA that was abnormally regulated in different tumors - in clinical tissues from patients with multiple myeloma (MM). The tumor tissues in which we assessed miR-32 expression levels were collected during our 5 years of clinical practice. Our study found an increase in miR-32 expression in MM tissues. Assessment of F-box and WD repeat domain-containing 7 (FBXW7) in MM tissues showed an inverse relation between the expression of FBXW7 and miR-32...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27696255/vision-statement-for-multiple-myeloma-future-directions
#4
Kenneth C Anderson
There has been great progress in the management and patient outcome in multiple myeloma due to the use of novel agents including immunomodulatory drugs and proteasome inhibitors; nonetheless, novel agents remain an urgent need. The three promising Achilles heals or vulnerabilities to be targetted in novel therapies include: protein degradation by the ubiquitin proteasome or aggresome pathways; restoring autologous antimyeloma immunity; and targeting aberrant biology resulting from constitutive and ongoing DNA damage in tumour cells...
2016: Cancer Treatment and Research
https://www.readbyqxmd.com/read/27677741/pharmacogenomics-and-chemical-library-screens-reveal-a-novel-scf-skp2-inhibitor-that-overcomes-bortezomib-resistance-in-multiple-myeloma
#5
E Malek, M A Y Abdel-Malek, S Jagannathan, N Vad, R Karns, A G Jegga, A Broyl, M van Duin, P Sonneveld, F Cottini, K C Anderson, J J Driscoll
While clinical benefit of the proteasome inhibitor (PI) bortezomib for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin (Ub) ligase Skp1-Cullin-1-Skp2 (SCF(Skp2)) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCF(Skp2) activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B...
September 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27672344/exposure-response-analysis-to-assess-the-concentration-qtc-relationship-of-cc-122
#6
Yan Li, Leonidas N Carayannopoulos, Michael Thomas, Maria Palmisano, Simon Zhou
CC-122 hydrochloride is a novel pleiotropic pathway modifier compound that binds cereblon, a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex. CC-122 has multiple activities including modulation of immune cells, antiproliferative activity of multiple myeloma and lymphoma cells, and antiangiogenic activity. CC-122 is being developed as an oncology treatment for hematologic malignancies and advanced solid tumors. Cardiovascular and vital sign assessments of CC-122 have been conducted in hERG assays in vitro and in a 28-day good laboratory practice monkey study with negative signals...
2016: Clinical Pharmacology: Advances and Applications
https://www.readbyqxmd.com/read/27530445/endothelin-1-et-1-induces-resistance-to-bortezomib-in-human-multiple-myeloma-cells-via-a-pathway-involving-the-etb-receptor-and-upregulation-of-proteasomal-activity
#7
Maria Vaiou, Evanthia Pangou, Panagiotis Liakos, Nikos Sakellaridis, George Vassilopoulos, Konstantinos Dimas, Christos Papandreou
PURPOSE: Bortezomib (BTZ) is used for the treatment of multiple myeloma (MM). However, a significant proportion of patients may be refractory to the drug. This study aimed to investigate whether the endothelin (ET-1) axis may act as an escape mechanism to treatment with bortezomib in MM cells. METHODS: NCI-H929 and RPMI-8226 (human MM cell lines) were cultured with or without ET-1, BTZ, and inhibitors of the endothelin receptors. ET-1 levels were determined by ELISA, while the protein levels of its receptors and of the PI3K and MAPK pathways' components by western blot...
October 2016: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/27492707/the-molecular-mechanism-of-thalidomide-analogs-in-hematologic-malignancies
#8
REVIEW
Stefanie Lindner, Jan Krönke
Thalidomide was sold in the 1950s as a sedative and was also used by pregnant women to treat morning sickness. It became notorious for causing severe birth defects and was removed from the market. More than four decades later, thalidomide had a renaissance in the treatment of cancer. Thalidomide and its more potent analogs, lenalidomide and pomalidomide, are nowadays approved treatments for multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. In addition, thalidomide and its analogs inhibit release of tumor necrosis factor-α and increase interleukin-2 (IL-2) and interferon-γ release from T cells...
August 5, 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/27472448/corrigendum-the-proteasome-deubiquitinase-inhibitor-vlx1570-shows-selectivity-for-ubiquitin-specific-protease-14-and-induces-apoptosis-of-multiple-myeloma-cells
#9
Xin Wang, Magdalena Mazurkiewicz, Ellin-Kristina Hillert, Maria Hägg Olofsson, Stefan Pierrou, Per Hillertz, Joachim Gullbo, Karthik Selvaraju, Aneel Paulus, Sharoon Akhtar, Felicitas Bossler, Asher Chanan Khan, Stig Linder, Padraig D'Arcy
No abstract text is available yet for this article.
2016: Scientific Reports
https://www.readbyqxmd.com/read/27460676/cereblon-and-its-downstream-substrates-as-molecular-targets-of-immunomodulatory-drugs
#10
REVIEW
Takumi Ito, Hiroshi Handa
Thalidomide was first developed as a sedative around 60 years ago, but exhibited teratogenicity, leading to serious defects such as limb deformities. Nevertheless, thalidomide is now recognized as a therapeutic drug for the treatment of Hansen's disease and myeloma. Immunomodulatory drugs (IMiDs), a new class of anti-cancer drug derived from thalidomide, have also been developed and exert potent anti-cancer effects. Although the molecular mechanism of thalidomide and IMiDs remained unclear for a long time, cereblon, a substrate receptor of the CRL4 E3 ubiquitin ligase was identified as a primary direct target by a new affinity technique...
September 2016: International Journal of Hematology
https://www.readbyqxmd.com/read/27413173/bortezomib-alleviates-experimental-pulmonary-hypertension-by-regulating-intracellular-calcium-homeostasis-in-pasmcs
#11
Jun Zhang, Wenju Lu, Yuqin Chen, Qian Jiang, Kai Yang, Meichan Li, Ziyi Wang, Xin Duan, Lei Xu, Haiyang Tang, Dejun Sun, Jian Wang
The ubiquitin-proteasome system is considered to be the key regulator of protein degradation. Bortezomib (BTZ) is the first proteasome inhibitor approved by the US Food and Drug Administration for treatment of relapsed multiple myeloma and mantle cell lymphoma. Recently, BTZ treatment was reported to inhibit right ventricular hypertrophy and vascular remodeling in hypoxia-exposed and monocrotaline-injected rats. However, the underlying mechanisms remain poorly understood. We previously confirmed that hypoxia-elevated basal intracellular Ca(2+) concentration ([Ca(2+)]i) and store-operated Ca(2+) entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs) are involved in pulmonary vascular remodeling...
September 1, 2016: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/27343012/cereblon-in-health-and-disease
#12
REVIEW
Hyoung Kyu Kim, Tae Hee Ko, Bayalagmaa Nyamaa, Sung Ryul Lee, Nari Kim, Kyung Soo Ko, Byoung Doo Rhee, Chul-Seung Park, Bernd Nilius, Jin Han
Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that has been linked to autosomal recessive non-syndromic mental retardation. Several key findings suggest diverse roles of CRBN, including its regulation of the large-conductance calcium- and voltage-activated potassium (BKCa) channels, regulation of thalidomide-binding proteins, and mediation of lenalidomide treatment in multiple myeloma. Recent studies also indicate that CRBN is involved in energy metabolism and negatively regulates AMP-activated protein kinase signaling...
August 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/27294876/immunomodulatory-drugs-disrupt-the-cereblon-cd147-mct1-axis-to-exert-antitumor-activity-and-teratogenicity
#13
Ruth Eichner, Michael Heider, Vanesa Fernández-Sáiz, Frauke van Bebber, Anne-Kathrin Garz, Simone Lemeer, Martina Rudelius, Bianca-Sabrina Targosz, Laura Jacobs, Anna-Maria Knorn, Jolanta Slawska, Uwe Platzbecker, Ulrich Germing, Christian Langer, Stefan Knop, Herrmann Einsele, Christian Peschel, Christian Haass, Ulrich Keller, Bettina Schmid, Katharina S Götze, Bernhard Kuster, Florian Bassermann
Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins...
July 2016: Nature Medicine
https://www.readbyqxmd.com/read/27284413/target-and-resistance-related-proteins-of-recombinant-mutant-human-tumor-necrosis-factor-related-apoptosis-inducing-ligand-on-myeloma-cell-lines
#14
Yuan Jian, Yuling Chen, Chuanying Geng, Nian Liu, Guangzhong Yang, Jinwei Liu, Xin Li, Haiteng Deng, Wenming Chen
Recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand (rmhTRAIL) has become a potential therapeutic drug for multiple myeloma (MM). However, the exact targets and resistance mechanisms of rmhTRAIL on MM cells remain to be elucidated. The present study aimed to investigate the target and resistance-related proteins of rmhTRAIL on myeloma cell lines. A TRAIL-sensitive myeloma cell line, RPMI 8226, and a TRAIL-resistance one, U266, were chosen and the differentially expressed proteins between the two cell lines were analyzed prior and subsequent to rmhTRAIL administration by a liquid chromatography-tandem mass spectrometry method...
June 2016: Biomedical Reports
https://www.readbyqxmd.com/read/27264969/the-proteasome-deubiquitinase-inhibitor-vlx1570-shows-selectivity-for-ubiquitin-specific-protease-14-and-induces-apoptosis-of-multiple-myeloma-cells
#15
Xin Wang, Magdalena Mazurkiewicz, Ellin-Kristina Hillert, Maria Hägg Olofsson, Stefan Pierrou, Per Hillertz, Joachim Gullbo, Karthik Selvaraju, Aneel Paulus, Sharoon Akhtar, Felicitas Bossler, Asher Chanan Khan, Stig Linder, Padraig D'Arcy
Inhibition of deubiquitinase (DUB) activity is a promising strategy for cancer therapy. VLX1570 is an inhibitor of proteasome DUB activity currently in clinical trials for relapsed multiple myeloma. Here we show that VLX1570 binds to and inhibits the activity of ubiquitin-specific protease-14 (USP14) in vitro, with comparatively weaker inhibitory activity towards UCHL5 (ubiquitin-C-terminal hydrolase-5). Exposure of multiple myeloma cells to VLX1570 resulted in thermostabilization of USP14 at therapeutically relevant concentrations...
June 6, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27155237/inhibition-of-chymotryptic-like-standard-proteasome-activity-exacerbates-doxorubicin-induced-cytotoxicity-in-primary-cardiomyocytes
#16
Eva-Margarete Spur, Nadine Althof, Dorota Respondek, Karin Klingel, Arnd Heuser, Hermen S Overkleeft, Antje Voigt
The anthracycline doxorubicin (DOX) is a potent anticancer agent for multiple myeloma (MM). A major limitation of this drug is the induction of death in cardiomyocytes leading to heart failure. Here we report on the role of the ubiquitin-proteasome system (UPS) as a critical surveillance pathway for preservation of cell vitality counteracting DOX treatment. Since in addition to DOX also suppression of proteasome activity is a rational therapeutic strategy for MM, we examined how small molecular compounds with clinically relevant proteasome subunit specificity affect DOX cytotoxicity...
April 15, 2016: Toxicology
https://www.readbyqxmd.com/read/27142104/expression-of-the-cereblon-binding-protein-argonaute-2-plays-an-important-role-for-multiple-myeloma-cell-growth-and-survival
#17
Qinqin Xu, Yue-xian Hou, Paul Langlais, Patrick Erickson, James Zhu, Chang-Xin Shi, Moulun Luo, Yuanxiao Zhu, Ye Xu, Lawrence J Mandarino, Keith Stewart, Xiu-bao Chang
BACKGROUND: Immunomodulatory drugs (IMiDs), such as lenalidomide, are therapeutically active compounds that bind and modulate the E3 ubiquitin ligase substrate recruiter cereblon, thereby affect steady-state levels of cereblon and cereblon binding partners, such as ikaros and aiolos, and induce many cellular responses, including cytotoxicity to multiple myeloma (MM) cells. Nevertheless, it takes many days for MM cells to die after IMiD induced depletion of ikaros and aiolos and thus we searched for other cereblon binding partners that participate in IMiD cytotoxicity...
2016: BMC Cancer
https://www.readbyqxmd.com/read/27141398/lenalidomide-enhances-antitumor-functions-of-chimeric-antigen-receptor-modified-t-cells
#18
Pavel Otáhal, Dana Průková, Vlastimil Král, Milan Fabry, Petra Vočková, Lucie Latečková, Marek Trněný, Pavel Klener
Tumor immunotherapy based on the use of chimeric antigen receptor modified T cells (CAR T cells) is a promising approach for the treatment of refractory hematological malignancies. However, a robust response mediated by CAR T cells is observed only in a minority of patients and the expansion and persistence of CAR T cells in vivo is mostly unpredictable.Lenalidomide (LEN) is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma, while it is clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype...
April 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27118409/targeting-proteasome-ubiquitin-receptor-rpn13-in-multiple-myeloma
#19
Y Song, A Ray, S Li, D S Das, Y T Tai, R D Carrasco, D Chauhan, K C Anderson
Proteasome inhibitor bortezomib is an effective therapy for relapsed and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance can limit its long-term utility. Recent research has focused on targeting ubiquitin receptors upstream of 20S proteasome, with the aim of generating less toxic therapies. Here we show that 19S proteasome-associated ubiquitin receptor Rpn13 is more highly expressed in MM cells than in normal plasma cells. Rpn13-siRNA (small interfering RNA) decreases MM cell viability...
September 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27012957/oral-proteasome-inhibitor-with-strong-preclinical-efficacy-in-myeloma-models
#20
Jonghoon Park, Eok Park, Cheol-Kyu Jung, Seung-Wan Kang, Byung Gyu Kim, Youngjoo Jung, Tae Hun Kim, Ji-Young Lim, Sung-Eun Lee, Chang-Ki Min, Kwang-Ai Won
BACKGROUND: The proteasome is a validated anti-cancer target and various small-molecule inhibitors are currently in clinical development or on the market. However, adverse events and resistance associated with those proteasome inhibitors indicate the need for a new generation of drugs. Therefore, we focused on developing an oral proteasome inhibitor with improved efficacy and safety profiles. METHOD: The in vitro inhibition of the 20S proteasome catalytic activities was determined in human multiple myeloma (MM) cellular lysates with fluorogenic peptide substrates specific for each catalytic subunit...
2016: BMC Cancer
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