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https://www.readbyqxmd.com/read/29720726/hri-mediated-translational-repression-reduces-proteotoxicity-and-sensitivity-to-bortezomib-in-human-pancreatic-cancer-cells
#1
Matthew C White, Rebecca D Schroeder, Keyi Zhu, Katherine Xiong, David J McConkey
Human cancer cells display extensive heterogeneity in their sensitivities to the proteasome inhibitor bortezomib (Velcade). The molecular mechanisms underlying this heterogeneity remain unclear, and strategies to overcome resistance are limited. Here, we discover that inherent differences in eIF2α phosphorylation among a panel of ten human pancreatic cancer cell lines significantly impacts bortezomib sensitivity, and implicate the HRI (heme-regulated inhibitor) eIF2α kinase as a novel therapeutic target. Within our panel, we identified a subset of cell lines with defective induction of eIF2α phosphorylation, conferring a high degree of sensitivity to bortezomib...
May 3, 2018: Oncogene
https://www.readbyqxmd.com/read/29706958/one-year-follow-up-of-natural-killer-cell-activity-in-multiple-myeloma-patients-treated-with-adjuvant-lenalidomide-therapy
#2
Laurie Besson, Emily Charrier, Lionel Karlin, Omran Allatif, Antoine Marçais, Paul Rouzaire, Lucie Belmont, Michel Attal, Christine Lombard, Gilles Salles, Thierry Walzer, Sébastien Viel
Multiple myeloma (MM) is a proliferation of tumoral plasma B cells that is still incurable. Natural killer (NK) cells can recognize and kill MM cells in vitro and can limit MM growth in vivo . Previous reports have shown that NK cell function is impaired during MM progression and suggested that treatment with immunomodulatory drugs (IMIDs) such as lenalidomide (LEN) could enhance it. However, the effects of IMIDs on NK cells have been tested mostly in vitro or in preclinical models and supporting evidence of their effect in vivo in patients is lacking...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29515774/unbiased-compound-protein-interface-mapping-and-prediction-of-chemoresistance-loci-through-forward-genetics-in-haploid-stem-cells
#3
Moritz Horn, Virginia Kroef, Kira Allmeroth, Nicole Schuller, Stephan Miethe, Martin Peifer, Josef M Penninger, Ulrich Elling, Martin S Denzel
Forward genetic screens in haploid mammalian cells have recently emerged as powerful tools for the discovery and investigation of recessive traits. Use of the haploid system provides unique genetic tractability and resolution. Upon positive selection, these screens typically employ analysis of loss-of-function (LOF) alleles and are thus limited to non-essential genes. Many relevant compounds, including anti-cancer therapeutics, however, target essential genes, precluding positive selection of LOF alleles. Here, we asked whether the use of random and saturating chemical mutagenesis might enable screens that identify essential biological targets of toxic compounds...
February 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29482577/inhibition-of-thioredoxin-activates-mitophagy-and-overcomes-adaptive-bortezomib-resistance-in-multiple-myeloma
#4
Zhihong Zheng, Shengjun Fan, Jing Zheng, Wei Huang, Cristina Gasparetto, Nelson J Chao, Jianda Hu, Yubin Kang
BACKGROUND: Although current chemotherapy using bortezomib (Velcade) against multiple myeloma in adults has achieved significant responses and even remission, a majority of patients will develop acquired resistance to bortezomib. Increased thioredoxin level has been reported to be associated with carcinogenesis; however, the role of thioredoxin in bortezomib drug resistance of myeloma remains unclear. METHODS: We generated several bortezomib-resistant myeloma cell lines by serially passaging with increased concentrations of bortezomib over a period of 1...
February 27, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29056470/phase-2-open-label-study-of-bortezomib-cladribine-and-rituximab-in-advanced-newly-diagnosed-and-relapsed-refractory-mantle-cell-and-indolent-lymphomas
#5
Soham D Puvvada, José Guillen-Rodriguez, Abhijeet Kumar, Lora Inclán, Kara Heard, Xavier I Rivera, Faiz Anwer, Jonathan H Schatz, Daruka Mahadevan, Daniel O Persky
BACKGROUND: Mantle-cell lymphoma (MCL) and indolent non-Hodgkin lymphoma (iNHL) are incurable heterogeneous diseases characterized by relapse. There is a need for newer treatments in MCL and iNHL, especially in the relapsed/refractory (R/R) setting. We therefore investigated the novel combination of bortezomib (Velcade), cladribine, and rituximab (VCR) in front-line and R/R settings in MCL and iNHL (NCT00980395). PATIENTS AND METHODS: Eligible patients included adults with biopsy-proven CD20-positive MCL and iNHL who met the criteria for treatment...
January 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28972650/characterization-of-a-rat-model-of-bortezomib-induced-painful-neuropathy
#6
Natalie A Duggett, Sarah J L Flatters
BACKGROUND AND PURPOSE: Bortezomib (Velcade®) is a breakthrough treatment for multiple myeloma, significantly improving patient survival. However, its use is limited by painful neuropathy often resulting in dose reduction/cessation of first-line treatment due to lack of treatment. The aim of this study was to characterize a clinically relevant rat model of bortezomib-induced painful neuropathy, using established evoked measures and novel ethological techniques, to aid drug discovery...
December 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28912868/bax-is-involved-in-the-anticancer-activity-of-velcade-in-colorectal-cancer
#7
Liya Su, Qimuge Suyila, Ling Yang, Hong Li, Yaguang Xi, Xiulan Su
Numerous chemotherapeutic agents promote tumor cell death by activating the intrinsic apoptosis signaling pathway. This pathway is regulated by mitochondrial dysfunction, which occurs through an intricate process controlled by complex interactions between B-cell lymphoma 2 (Bcl-2) family members and other cellular proteins. Bcl-2-associated X protein (Bax) is a proapoptotic protein that is an essential component of the intrinsic apoptosis signaling pathway. Patients lacking Bax may be less sensitive to chemotherapy due to an impaired intrinsic apoptosis signaling pathway...
October 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28558940/hyperthermia-enhances-bortezomib-induced-apoptosis-in-human-white-blood-cancer-cells
#8
Timur Saliev, Loreto B Feril, Dinara Begimbetova, Dinara Baiskhanova, Anton Klodzinskyi, Xeniya Bobrova, Rassulbek Aipov, Tolkyn Baltabayeva, Katsuro Tachibana
At present, the current therapeutic strategy for apoptosis induction mainly relies on the administration of pharmacological apoptotic modulators. Apart from that, apoptosis can be induced by various external stimuli such as hyperthermia, ionizing radiation, and electric fields. Despite advantages, both physical and pharmacological approaches bear some limitations as well. The rationale of this study was to overcome the limitations by combining hyperthermia and apoptotic modulator 'bortezomib' (Velcade). Two types of human blood cancer cell lines were utilized: human leukemic monocyte lymphoma cell U937 line and peripheral blood mononuclear cells (PMBCs) derived from the patient diagnosed with acute myeloid leukemia...
July 2017: Journal of Thermal Biology
https://www.readbyqxmd.com/read/28445949/lmp1-slamf1high-cells-are-associated-with-drug-resistance-in-epstein-barr-virus-positive-farage-cells
#9
Heejei Yoon, Young Hyeh Ko
How Epstein-Barr virus (EBV) affects the clinical outcome of EBV-positive diffuse large B-cell lymphoma (DLBCL) remains largely unknown. The viral oncogene LMP1 is at the crux of tumorigenesis and cell survival. Therefore, we examined the association between LMP1high cells drug resistance. We first assessed SLAMF1 as a surrogate marker for LMP1high cells. LMP1 and its target gene CCL22 were highly expressed in SLAMF1high Farage cells. These cells survived longer following treatment with a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28435528/discovery-of-highly-selective-inhibitors-of-the-immunoproteasome-low-molecular-mass-polypeptide-2-lmp2-subunit
#10
Henry W B Johnson, Janet L Anderl, Erin K Bradley, John Bui, Jeffrey Jones, Shirin Arastu-Kapur, Lisa M Kelly, Eric Lowe, David C Moebius, Tony Muchamuel, Christopher Kirk, Zhengping Wang, Dustin McMinn
Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition in vivo...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28408721/decarboxylative-borylation
#11
Chao Li, Jie Wang, Lisa M Barton, Shan Yu, Maoqun Tian, David S Peters, Manoj Kumar, Antony W Yu, Kristen A Johnson, Arnab K Chatterjee, Ming Yan, Phil S Baran
The widespread use of alkyl boronic acids and esters is frequently hampered by the challenges associated with their preparation. We describe a simple and practical method to rapidly access densely functionalized alkyl boronate esters from abundant carboxylic substituents. This broad-scope nickel-catalyzed reaction uses the same activating principle as amide bond formation to replace a carboxylic acid moiety with a boronate ester. Application to peptides allowed expedient preparations of α-amino boronic acids, often with high stereoselectivity, thereby facilitating synthesis of the alkyl boronic acid drugs Velcade and Ninlaro as well as a boronic acid version of the iconic antibiotic vancomycin...
June 9, 2017: Science
https://www.readbyqxmd.com/read/28327055/the-evaluation-of-the-anti-cancer-activity-of-ixazomib-on-caco2-colon-solid-tumor-cells-comparison-with-bortezomib
#12
Selin Engür, Miriş Dikmen
Proteasome inhibition has recently emerged as a clinically effective anticancer therapeutic approach. The first proteasome inhibitor, bortezomib (Velcade, PS-341), and new proteasome inhibitors including ixazomib have become more important in the development of targeted cancer therapies. Under physiological conditions, MLN9708 (ixazomib citrate), the stable citrate ester drug substance, hydrolyzes rapidly to MLN2238 (ixazomib), the biologically active boronic acid. It is a second-generation proteasome inhibitor, similar to the well-known proteasome inhibitor bortezomib, which is currently being investigated in phase 3 trials as a treatment for multiple Myeloma...
March 22, 2017: Acta Clinica Belgica
https://www.readbyqxmd.com/read/28322099/clinical-analysis-of-40-multiple-myeloma-patients-with-extramedullary-plasmacytoma-of-the-head
#13
Wan-Jun Sun, Jia-Jia Zhang, Na An, Men Shen, Zhong-Xia Huang, Xin Li
Objectives To investigate the clinical characteristics, survival and prognosis of patients with multiple myeloma (MM) and head extramedullary plasmacytoma (EMP). Methods Forty MM patients were enrolled in the study (18 men, 22 women; median age, 55 years). Results Median overall survival (OS) and progression-free survival (PFS) were 24 (5-78) months and 17 (2-36) months, respectively. The 2-, 3- and 5-year OS rates were 51%, 20% and 7%, respectively. The 2-year PFS was 15%. Median OS and PFS in patients administered velcade were 26 (18-50) and 22...
December 2016: Journal of International Medical Research
https://www.readbyqxmd.com/read/28256432/phase-ii-study-of-dose-attenuated-bortezomib-cyclophosphamide-and-dexamethasone-vcd-lite-in-very-old-or-otherwise-toxicity-vulnerable-adults-with-newly-diagnosed-multiple-myeloma
#14
Sascha A Tuchman, Joseph O Moore, Carlos D DeCastro, Zhiguo Li, Emily Sellars, Yubin Kang, Gwynn Long, Cristina G Gasparetto
OBJECTIVES: Multiple myeloma (MM) primarily strikes older adults, but full-dose chemotherapy such as bortezomib (Velcade), cyclophosphamide and dexamethasone (VCD) is often excessively toxic to very old or frail adults and those with substantial comorbidities. We piloted dose-attenuated VCD ("VCD-Lite") in such vulnerable adults with newly diagnosed MM (NDMM). MATERIALS AND METHODS: Subjects with NDMM and a high risk of therapy-related toxicity due to factors above received bortezomib 1...
May 2017: Journal of Geriatric Oncology
https://www.readbyqxmd.com/read/28036258/epstein-barr-virus-ebna2-directs-doxorubicin-resistance-of-b-cell-lymphoma-through-ccl3-and-ccl4-mediated-activation-of-nf-%C3%AE%C2%BAb-and-btk
#15
Joo Hyun Kim, Won Seog Kim, Jung Yong Hong, Kung Ju Ryu, Seok Jin Kim, Chaehwa Park
Epstein-Barr virus (EBV)-encoded nuclear antigen, EBNA2, expressed in EBV-infected B lymphocytes is critical for lymphoblastoid cell growth. Microarray profiling and cytokine array screening revealed that EBNA2 is associated with upregulation of the chemokines CCL3 and CCL4 in lymphoma cells. Depletion or inactivation of CCL3 or CCL4 sensitized DLBCL cells to doxorubicin. Our results indicate that EBV influences cell survival via an autocrine mechanism whereby EBNA2 increases CCL3 and CCL4, which in turn activate the Btk and NF-κB pathways, contributing to doxorubicin resistance of B lymphoma cells...
January 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28003640/induction-of-apoptosis-in-u937-cells-by-using-a-combination-of-bortezomib-and-low-intensity-ultrasound
#16
Timur Saliev, Loreto B Feril, Koichi Ogawa, Akiko Watanabe, Dinara Begimbetova, Askhat Molkenov, Dauren Alimbetov, Katsuro Tachibana
BACKGROUND We scrutinized the feasibility of apoptosis induction in blood cancer cells by means of low-intensity ultrasound and the proteasome inhibitor bortezomib (Velcade). MATERIAL AND METHODS Human leukemic monocyte lymphoma U937 cells were subjected to ultrasound in the presence of bortezomib and the echo contrast agent Sonazoid. Two types of acoustic intensity (0.18 W/cm² and 0.05 W/cm²) were used for the experiments. Treated U937 cells were analyzed for viability and levels of early and late apoptosis...
December 22, 2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/27698861/igm-multiple-myeloma-with-an-extremely-rare-non-aggressive-presentation-a-case-report
#17
Thomas Greuter, Martin Browne, Corina Dommann-Scherrer, Daniel Binder, Christoph Renner, Ursula Kapp
In the present study, the case of a 41-year-old man with immunoglobulin (Ig)M multiple myeloma (MM) that presented with an unusually non-aggressive clinical course who has survived for >9 years to date, is presented. Initial diagnosis of symptomatic MM was established according to the International Myeloma Working Group consensus statement and guidelines. Due to the mild symptoms, no therapy was administered and the patient was closely followed up. Eight years after initial diagnosis, clinical, morphological and genetic progression occurred with the development of hypercalcemia, progressively deteriorating polyneuropathy, clonal expansion of plasma cells up to 50% of hematopoietic cells and demonstration of the typical t(11;14) translocation (Ig heavy chain locus rearrangement)...
October 2016: Oncology Letters
https://www.readbyqxmd.com/read/27455953/bcl-b-bcl2l10-is-overexpressed-in-patients-suffering-from-multiple-myeloma-mm-and-drives-an-mm-like-disease-in-transgenic-mice
#18
Mohamed-Amine Hamouda, Arnaud Jacquel, Guillaume Robert, Alexandre Puissant, Valentine Richez, Romeo Cassel, Nina Fenouille, Sandrine Roulland, Jerome Gilleron, Emmanuel Griessinger, Alix Dubois, Beatrice Bailly-Maitre, Diogo Goncalves, Aude Mallavialle, Pascal Colosetti, Sandrine Marchetti, Martine Amiot, Patricia Gomez-Bougie, Nathalie Rochet, Marcel Deckert, Herve Avet-Loiseau, Paul Hofman, Jean-Michel Karsenti, Pierre-Yves Jeandel, Claudine Blin-Wakkach, Bertrand Nadel, Thomas Cluzeau, Kenneth C Anderson, Jean-Gabriel Fuzibet, Patrick Auberger, Frederic Luciano
Multiple myeloma (MM) evolves from a premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS). However, the factors underlying the malignant transformation of plasmocytes in MM are not fully characterized. We report here that Eµ-directed expression of the antiapoptotic Bcl-B protein in mice drives an MM phenotype that reproduces accurately the human disease. Indeed, with age, Eµ-bcl-b transgenic mice develop the characteristic features of human MM, including bone malignant plasma cell infiltration, a monoclonal immunoglobulin peak, immunoglobulin deposit in renal tubules, and highly characteristic bone lytic lesions...
August 22, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27441522/diarrhea-in-multiple-myeloma-a-review-of-the-literature
#19
REVIEW
Beth Faiman
BACKGROUND: One of the most common and inadequately managed symptoms that patients with multiple myeloma (MM) experience as a result of cancer treatment is diarrhea. Diarrhea in patients with MM often is severe enough to warrant dose reduction, delays, or discontinuation of chemotherapy. Short-term diarrhea can occur as a side effect of drugs, such as bortezomib (Velcade®) or panobinostat (Farydak®). Late-onset diarrhea from lenalidomide (Revlimid®) can occur 17-24 months after the start of therapy...
August 1, 2016: Clinical Journal of Oncology Nursing
https://www.readbyqxmd.com/read/27381943/platinum-containing-compound-platinum-pyrithione-is-stronger-and-safer-than-cisplatin-in-cancer-therapy
#20
COMPARATIVE STUDY
Chong Zhao, Xin Chen, Dan Zang, Xiaoying Lan, Siyan Liao, Changshan Yang, Peiquan Zhang, Jinjie Wu, Xiaofen Li, Ningning Liu, Yuning Liao, Hongbiao Huang, Xianping Shi, Lili Jiang, Xiuhua Liu, Zhimin He, Xuejun Wang, Jinbao Liu
DNA is the well-known molecular target of current platinum-based anticancer drugs; consequently, their clinical use is severely restricted by their systemic toxicities and drug resistance originating from non-selective DNA damage. Various strategies have been developed to circumvent the shortcomings of platinum-based chemotherapy but the inherent problem remains unsolved. Here we report that platinum pyrithione (PtPT), a chemically well-characterized synthetic complex of platinum, inhibits proteasome function and thereby exhibits greater and more selective cytotoxicity to multiple cancer cells than cisplatin, without showing discernible DNA damage both in vitro and in vivo...
September 15, 2016: Biochemical Pharmacology
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