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Ubiquitin myeloma

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https://www.readbyqxmd.com/read/28205024/immunomodulatory-drugs-in-multiple-myeloma-mechanisms-of-action-and-clinical-experience
#1
REVIEW
Sarah A Holstein, Philip L McCarthy
Over the last two decades, the outcomes for patients with multiple myeloma, a plasma cell malignancy, have dramatically improved. The development of the immunomodulatory drugs (IMiDs), which include thalidomide, lenalidomide, and pomalidomide, has contributed significantly to these improved outcomes. While thalidomide is now less commonly prescribed, lenalidomide is widely used in the treatment of newly diagnosed transplant-eligible and transplant-ineligible patients, in the maintenance setting post-transplant and in the relapsed/refractory setting, while pomalidomide is currently utilized in the relapsed/refractory setting...
February 16, 2017: Drugs
https://www.readbyqxmd.com/read/28196975/tyropeptins-proteasome-inhibitors-produced-by-kitasatospora-sp-mk993-df2
#2
REVIEW
Isao Momose, Takumi Watanabe
Tyropeptins are new proteasome inhibitors isolated from the culture broth of Kitasatospora sp. MK993-dF2. Tyropeptins permeate cell membranes, inhibit intracellular proteasomes and reduce the degradation of ubiquitinated proteins in mammalian cells. We performed structure-based drug design and structure-activity relationship studies on tyropeptin derivatives to obtain valuable information of derivatives. Among the synthesized tyropeptin derivatives, some boronic acid derivatives exhibited potent antitumor effects against human multiple myeloma...
February 15, 2017: Journal of Antibiotics
https://www.readbyqxmd.com/read/28191850/discovery-of-an-inhibitor-of-the-proteasome-subunit-rpn11
#3
Christian Perez, Jing Li, Francesco Parlati, Matthieu Rouffet, Yuyong Ma, Andrew L Mackinnon, Tsui-Fen Chou, Raymond J Deshaies, Seth M Cohen
The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have been validated in the treatment of multiple myeloma, with several FDA-approved therapeutics. Rpn11 is a Zn(2+)-dependent metalloisopeptidase that hydrolyzes ubiquitin from tagged proteins that are trafficked to the proteasome for degradation...
February 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28117417/proteasome-inhibitors-in-cancer-therapy
#4
REVIEW
Elisabet E Manasanch, Robert Z Orlowski
The ubiquitin proteasome pathway was discovered in the 1980s to be a central component of the cellular protein-degradation machinery with essential functions in homeostasis, which include preventing the accumulation of misfolded or deleterious proteins. Cancer cells produce proteins that promote both cell survival and proliferation, and/or inhibit mechanisms of cell death. This notion set the stage for preclinical testing of proteasome inhibitors as a means to shift this fine equilibrium towards cell death...
January 24, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28087699/activation-of-c-abl-kinase-potentiates-the-anti-myeloma-drug-lenalidomide-by-promoting-dda1-recruitment-to-the-crl4-ubiquitin-ligase
#5
Shaobing Gao, Chenlu Geng, Tianyu Song, Xuanru Lin, Jiye Liu, Zhen Cai, Yong Cang
Cullin Ring Ligase 4 (CRL4), a complex of Cul4 and DDB1, regulates cell cycle, DNA damage repair, and chromatin replication by targeting a variety of substrates for ubiquitination. CRL4 is also hijacked by viral proteins or thalidomide-derived compounds to degrade host restriction factors. Here we report that the c-Abl non-receptor kinase phosphorylates DDB1 at residue Y316 to recruit a small regulatory protein DDA1, leading to increased substrate ubiquitination. Pharmacological inhibition or genetic ablation of the Abl-DDB1-DDA1 axis decreases the ubiquitination of CRL4 substrates, including IKZF1 and IKZF3 in lenalidomide-treated multiple myeloma cells...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28079010/discovery-of-natural-product-proteasome-inhibitors-as-novel-anticancer-therapeutics-current-status-and-perspectives
#6
Hui Wang, Qingzhu Yang, Ping Dou, Huanjie Yang
Natural products serve as a main resource for drug discovery. The ubiquitin-proteasome system (UPS) is one of the primary intracellular protein degradation systems, which is responsible for the degradation of most short-lived, mis-folded and aged proteins. The proteasome is a validated target for cancer treatment, since cancer cells are more reliant on high levels of proteasome activity to maintain the dynamic protein homeostasis required for enhanced metabolism and unrestricted proliferation inherent in cancer cells...
January 11, 2017: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/28017969/ikzf1-expression-is-a-prognostic-marker-in-newly-diagnosed-standard-risk-multiple-myeloma-treated-with-lenalidomide-and-intensive-chemotherapy-a-study-of-the-german-myeloma-study-group-dsmm
#7
J Krönke, F Kuchenbauer, M Kull, V Teleanu, L Bullinger, D Bunjes, A Greiner, S Kolmus, S Köpff, M Schreder, L-O Mügge, C Straka, M Engelhardt, H Döhner, H Einsele, F Bassermann, R Bargou, S Knop, C Langer
Lenalidomide is an immunomodulatory compound with high clinical activity in multiple myeloma. Lenalidomide binding to the Cereblon (CRBN) E3 ubiquitin ligase results in targeted ubiquitination and degradation of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) leading to growth-inhibition of multiple myeloma cells. Recently, Basigin (BSG) was identified as another protein regulated by CRBN that is involved in the activity of lenalidomide. Here, we analyzed the prognostic value of IKZF1, IKZF3, CRBN and BSG mRNA expression levels in pretreatment plasma cells from sixty patients with newly diagnosed multiple myeloma uniformly treated with lenalidomide in combination with intensive chemotherapy within a clinical trial...
December 26, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28000886/hsa-mir-631-resensitizes-bortezomib-resistant-multiple-myeloma-cell-lines-by-inhibiting-ubch10
#8
Hao Xi, Lu Li, Juan Du, Ran An, Rong Fan, Jing Lu, Yin-Xiang Wu, Shu-Xie Wu, Jian Hou, Li-Ming Zhao
Although bortezomib (BTZ) remains a first-line agent for multiple myeloma (MM) therapy, the development of BTZ resistance has become an indicator of poor prognosis in MM patients. It is thus urgent to develop strategies to restore the vulnerability of MM to BTZ. This study demonstrated, for the first time, that UbcH10 is highly expressed in BTZ-resistant myeloma cell lines U-266/BTZ, NCI-H929/BTZ and RPMI-8226/BTZ, which is attributed to the inactivation of post-transcriptional control. The in-depth study revealed that during the development of BTZ resistance in these cells, the hsa-miR-631 levels were decreased, which resulted in the increased expression of the target gene UbcH10...
February 2017: Oncology Reports
https://www.readbyqxmd.com/read/27917682/the-preclinical-discovery-and-development-of-bortezomib-for-the-treatment-of-mantle-cell-lymphoma
#9
Richard Arkwright, Tri Minh Pham, Jeffrey A Zonder, Q Ping Dou
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 20, 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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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...
December 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
#17
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
#18
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
#19
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
#20
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
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