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https://www.readbyqxmd.com/read/29342125/induction-of-pro-apoptotic-endoplasmic-reticulum-stress-in-multiple-myeloma-cells-by-neo214-perillyl-alcohol-conjugated-to-rolipram
#1
Thomas C Chen, Nymph Chan, Shirin Labib, Jiali Yu, Hee-Yeon Cho, Florence M Hofman, Axel H Schönthal
Despite the introduction of new therapies for multiple myeloma (MM), many patients are still dying from this disease and novel treatments are urgently needed. We have designed a novel hybrid molecule, called NEO214, that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH), an inducer of endoplasmic reticulum (ER) stress, to rolipram (Rp), an inhibitor of phosphodiesterase-4 (PDE4). Its potential anticancer effects were investigated in a panel of MM cell lines. We found that NEO214 effectively killed MM cells in vitro with a potency that was over an order of magnitude stronger than that of its individual components, either alone or in combination...
January 17, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29340073/ym155-exerts-potent-cytotoxic-activity-against-quiescent-g0-g1-multiple-myeloma-and-bortezomib-resistant-cells-via-inhibition-of-survivin-and-mcl-1
#2
Miyuki Ookura, Tatsuya Fujii, Hideki Yagi, Takuya Ogawa, Shinji Kishi, Naoko Hosono, Hiroko Shigemi, Takahiro Yamauchi, Takanori Ueda, Akira Yoshida
YM155, a novel small molecule inhibitor of survivin, shows broad anticancer activity. Here, we have focused on the cytotoxic activity of YM155 against multiple myeloma (MM) including cytokinetically quiescent (G0/G1) cells and bortezomib resistant cells. YM155 strongly inhibited the growth of MM cell lines with the IC50 value of below 10 nM. YM155 also showed potent anti-myeloma activity in mouse xenograft model. YM155 suppressed the expression of survivin and rapidly directed Mcl-1 protein for proteasome degradation...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339053/upregulation-of-nlrp3-via-stat3-dependent-histone-acetylation-contributes-to-painful-neuropathy-induced-by-bortezomib
#3
Cui-Cui Liu, Zhu-Xi Huang, Xiao Li, Kai-Feng Shen, Meng Liu, Han-Dong Ouyang, Su-Bo Zhang, Yu-Ting Ruan, Xiao-Long Zhang, Shao-Ling Wu, Wen-Jun Xin, Chao Ma
Painful neuropathy, as a severe side effect of chemotherapeutic bortezomib, is the most common reason for treatment discontinuation. However, the mechanism by which administration of bortezomib leads to painful neuropathy remains unclear. In the present study, we found that application of bortezomib significantly increased the expression of NOD-like receptor family pyrin domain containing 3 (NLRP3) and phosphorylated signal transducer and activator of transcription-3 (STAT3) in dorsal root ganglion (DRG). Intrathecal injection of NLRP3 siRNA significantly prevented the mechanical allodynia induced by bortezomib treatment, and intrathecal injection of recombinant adeno-associated virus vector encoding NLRP3 markedly decreased paw withdrawal threshold of naive rats...
January 12, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29338540/efficacy-and-safety-of-frontline-rituximab-cyclophosphamide-doxorubicin-and-prednisone-plus-bortezomib-vr-cap-or-vincristine-r-chop-in-a-subset-of-newly-diagnosed-mantle-cell-lymphoma-patients-medically-eligible-for-transplantation-in-the-randomized-phase-3
#4
Johannes Drach, Huiqiang Huang, Olga Samoilova, Andrew Belch, Charles Farber, André Bosly, Jan Novak, Jan Zaucha, Angela Dascalescu, Udomsak Bunworasate, Zvenyslava Masliak, Kateryna Vilchevskaya, Tadeusz Robak, Lixia Pei, Brendan Rooney, Helgi van de Velde, Franco Cavalli
This post-hoc subanalysis of the LYM-3002 phase 3 study assessed the efficacy and safety of substituting vincristine in rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHOP; n = 42) for bortezomib (VR-CAP; n = 38) in a subgroup of 80 mantle cell lymphoma (MCL) patients aged <60 years who did not receive stem cell transplantation (SCT) despite medical eligibility. Complete response (CR)/unconfirmed CR (CRu) rates were 67 vs. 39% (odds ratio 3.69 [95% CI(confidence interval): 1.31, 10...
January 17, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29334316/potential-therapeutic-and-economic-value-of-risk-stratified-treatment-as-initial-treatment-of-multiple-myeloma-in-europe
#5
Jennifer G Gaultney, Therese W Ng, Carin A Uyl-de Groot, Pieter Sonneveld, Erik H van Beers, Martin H van Vliet, William K Redekop
Biomarkers associated with prognosis in multiple myeloma (MM) can be used to stratify patients into risk categories. An attractive alternative to uniform treatment (UT), risk-stratified treatment (RST) is proposed where high-risk patients receive bortezomib-based regimens while standard-risk patients receive alternative less costly regimens. An early Markov-type decision analytic model evaluated the potential therapeutic and economic value of different RST strategies compared with UT in MM patients in key European countries...
January 15, 2018: Pharmacogenomics
https://www.readbyqxmd.com/read/29333597/tp53-polymorphism-in-plasma-cell-myeloma
#6
Szymon Andrzej Zmorzynski, Iwona Korszen-Pilecka, Magdalena Wojcierowska-Litwin, Barbara Kwiatkowska-Drabik, Malgorzata Luterek, Sylwia Chocholska, Dorota Koczkodaj, Sylwia Popek, Malgorzata Michalak-Wojnowska, Grazyna Swiderska-Kolacz, Joanna Januszewska, Iwona Surowiec, Waldemar Tomczak, Marek Hus, Anna Dmoszynska, Marcin Pasiarski, Katarzyna Poniewierska-Jasak, Katarzyna Cieplinska, Olga Jankowska-Lecka, Agata Anna Filip
INTRODUCTION: Significant and accessible predictive factors for bortezomib treatment in plasma cell myeloma (PCM) are still lacking. TP53 codon 72 polymorphism (P72R) results in proline (P) or arginine (R) at 72 amino acid position, which causes synthesis of proteins with distinct functions. The aims of our study were to: 1) analyze whether this polymorphism is associated with an increased risk of PCM; 2) study whether the P72R polymorphism affects overall survival (OS) among PCM patients; 3) assess the possible association of the P72R polymorphism with sensitivity to bortezomib in cell cultures derived from PCM patients...
January 15, 2018: Folia Histochemica et Cytobiologica
https://www.readbyqxmd.com/read/29330435/beta-catenin-cleavage-enhances-transcriptional-activation
#7
Tatiana Goretsky, Emily M Bradford, Qing Ye, Olivia F Lamping, Tomas Vanagunas, Mary Pat Moyer, Patrick C Keller, Preetika Sinh, Josep M Llovet, Tianyan Gao, Qing-Bai She, Linheng Li, Terrence A Barrett
Nuclear activation of Wnt/β-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that β-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of β-catenin phosphorylated at serine 552 (pβ-Cat552). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pβ-Cat552, increased to the exclusion of full size (FS) forms of β-catenin. LMW β-catenin lacks both termini, leaving residues in the armadillo repeat intact...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29327347/unique-anti-myeloma-activity-by-thiazolidine-2-4-dione-compounds-with-pim-inhibiting-activity
#8
Shiro Fujii, Shingen Nakamura, Asuka Oda, Hirokazu Miki, Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Ariunzaya Bat-Erdene, Yusaku Maeda, Masahiro Oura, Mamiko Takahashi, Masami Iwasa, Itsuro Endo, Sumiko Yoshida, Ken-Ichi Aihara, Kiyoe Kurahashi, Takeshi Harada, Kumiko Kagawa, Michiyasu Nakao, Shigeki Sano, Masahiro Abe
Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447...
January 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29326124/bortezomib-based-immunosuppression-after-reduced-intensity-conditioning-hematopoietic-stem-cell-transplantation-randomized-phase-ii-results
#9
John Koreth, Haesook T Kim, Paulina B Lange, Samuel J Poryanda, Carol G Reynolds, Sharmila Chamling Rai, Philippe Armand, Corey S Cutler, Vincent T Ho, Brett Glotzbecker, Rushdia Yusuf, Sarah Nikiforow, Yi-Bin Chen, Bimalangshu Dey, Malgorzata McMasters, Jerome Ritz, Bruce R Blazar, Robert J Soiffer, Joseph H Antin, Edwin P Alyea
A prior phase I/II trial of bortezomib/tacrolimus/methotrexate prophylaxis after HLA-mismatched reduced intensity conditioning allogeneic hematopoietic stem cell transplantation documented low acute graft versus host disease incidence, with promising overall and progression-free survival. We performed an open-label 3-arm 1:1:1 phase II randomized-controlled-trial comparing grade II-IV acute graft versus host disease between conventional tacrolimus/methotrexate (A) versus bortezomib/tacrolimus/methotrexate (B); and versus bortezomib/sirolimus/tacrolimus (C), in reduced intensity conditioning allogeneic transplantation recipients lacking HLA-matched related donors...
January 11, 2018: Haematologica
https://www.readbyqxmd.com/read/29326121/modeling-multiple-myeloma-bone-marrow-interactions-and-response-to-drugs-in-a-3d-surrogate-microenvironment
#10
Daniela Belloni, Silvia Heltai, Maurilio Ponzoni, Antonello Villa, Barbara Vergani, Lorenza Pecciarini, Magda Marcatti, Stefania Girlanda, Giovanni Tonon, Fabio Ciceri, Federico Caligaris-Cappio, Marina Ferrarini, Elisabetta Ferrero
Multiple myeloma develops primarily inside the bone marrow microenvironment, that confers pro-survival signals and drug resistance. 3D cultures that reproduce multiple myeloma-bone marrow interactions are needed to fully investigate multiple myeloma pathogenesis and response to drugs. To this purpose, we exploited the 3D Rotary Cell Culture System bioreactor technology for myeloma-bone marrow co-cultures in gelatin scaffolds. The model was validated with myeloma cell lines that, as assessed by histochemical and electron-microscopic analyses, engaged contacts with stromal cells and endothelial cells...
January 11, 2018: Haematologica
https://www.readbyqxmd.com/read/29320913/a-phase-2-study-of-rituximab-cyclophosphamide-bortezomib-and-dexamethasone-r-cybord-in-relapsed-low-grade-and-mantle-cell-lymphoma
#11
Mohamad Bassam Sonbol, Talal Hilal, Amylou C Dueck, Allison C Rosenthal, Christopher R Conley, Heidi E Kosiorek, Brenda F Ginos, Katherine M Gano, Craig S Nichols, Jose F Leis, Patrick B Johnston, Thomas M Habermann, Donald W Northfelt, Peter Leif Bergsagel, David J Inwards, Thomas E Witzig, Stephen M Ansell, Craig B Reeder
In this phase 2 trial, we sought to evaluate the efficacy and safety of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBorD) in patients with low-grade NHL. The regimen included rituximab on day 1 with weekly cyclophosphamide, dexamethasone, and bortezomib 1.3 mg/m2 IV in a 28-day cycle. Twenty one patients were enrolled on the study. Median age was 69 years (range 51-80) and 17 (81%) patients had two or more prior treatments. Histologies included FL (n = 8), MCL (n = 8), and LPL/WM (n = 5)...
January 10, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29318562/targeting-deubiquitinases-in-cancer
#12
Joseph S Bednash, Rama K Mallampalli
The ubiquitin-proteasome system (UPS) is a complex and robust metabolic pathway that contributes to the regulation of many key cellular processes including the cell cycle, cell division, and response to external stimuli. Ubiquitin ligases, which tag proteins with ubiquitin, are opposed by deubiquitinase enzymes (DUBs). The relative activity of these enzymes allows for a dynamic balance that determines the abundance and activity of cellular proteins. Targeting the UPS in cancer has proven successful, as evidenced by use of bortezomib, a proteasome inhibitor, in multiple myeloma...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29317395/the-role-of-elotuzumab-in-the-treatment-of-relapsed-or-refractory-multiple-myeloma
#13
REVIEW
Jill M Comeau, Katherine Kelly, Gary W Jean
PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy and safety, cost, and place in therapy of elotuzumab for treatment of relapsed or refractory multiple myeloma (MM) are reviewed. SUMMARY: Elotuzumab is a humanized monoclonal antibody that targets the signaling lymphocytic activation molecule (SLAM) protein SLAMF7 and facilitates an antibody-dependent cellular cytotoxicity interaction between myeloma cells and natural killer cells. Elotuzumab has U.S...
January 15, 2018: American Journal of Health-system Pharmacy: AJHP
https://www.readbyqxmd.com/read/29315141/the-treatment-of-antibody-mediated-rejection-in-kidney-transplantation-an-updated-systematic-review-and-meta-analysis
#14
Susan S Wan, Tracey D Ying, Kate Wyburn, Darren M Roberts, Melanie Wyld, Steven J Chadban
BACKGROUND: Current treatments for antibody-mediated rejection (AMR) in kidney transplantation are based on low-quality data from a small number of controlled trials. Novel agents targeting B-cells, plasma-cells and the complement system have featured in recent studies of AMR. METHODS: We conducted a systematic review and meta-analysis of controlled trials in kidney transplant recipients using Medline, EMBASE and CENTRAL from inception to February 2017. RESULTS: Of 14,380 citations we identified 21 studies, including 10 randomized controlled trials, involving 751 participants...
January 8, 2018: Transplantation
https://www.readbyqxmd.com/read/29305109/scriptaid-inhibits-cell-survival-cell-cycle-and-promotes-apoptosis-in-multiple-myeloma-via-epigenetic-regulation-of-p21
#15
Ruosi Yao, Danyang Han, Xiaoyang Sun, Yu Xie, Qingyun Wu, Chunling Fu, Yao Yao, Hujun Li, Zhenyu Li, Kailin Xu
Multiple myeloma (MM) is an extremely serious plasma cell malignancy. Despite recent introduction of chemotherapies such as bortezomib and lenalidomide, it remains an incurable disease due to high rate of relapse and development of drug resistance. Epigenetic regulation is closely related with MM progression; nevertheless, the epigenetic modification mechanism of myeloma cell apoptosis has remained unclear. As a novel histone deacetylase inhibitor, Scriptaid's possible roles in MM progression have not been explored...
January 2, 2018: Experimental Hematology
https://www.readbyqxmd.com/read/29305052/progress-curve-analysis-of-the-kinetics-of-slow-binding-anticancer-drug-inhibitors-of-the-20s-proteasome
#16
Brian B Hasinoff
Bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib are anticancer drugs that target the proteasomal system. Carfilzomib and oprozomib are epoxyketones that form an irreversible covalent bond with the 20S proteasome, whereas bortezomib, ixazomib, and delanzomib are boronic acids that form slowly reversible adducts. The binding kinetics of some of these drugs have either not been well characterized, or have been studied under a variety of different conditions. Utilizing a fluorogenic substrate the kinetics of the slow-binding inhibition of the chymotrypsin-like proteasomal activity of human 20S proteasome was determined under a standard set of conditions in order to compare the kinetic and equilibrium properties of these drugs...
January 2, 2018: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29304284/-n-hydroxycarbonylbenylamino-quinolines-as-selective-histone-deacetylase-6-inhibitors-suppress-growth-of-multiple-myeloma-in-vitro-and-in-vivo
#17
Hsueh-Yun Lee, Kunal Nepali, Fang-I Huang, Chih-Yi Chang, Mei-Jung Lai, Yu-Hsuan Li, Hsiang-Ling Huang, Chia-Ron Yang, Jing-Ping Liou
A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7-31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC50 value of 0.29 nM, which is 4000-43000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferative activity against human multiple myeloma RPMI 8226, U266, and NCI-H929 cells with no effect on normal bone marrow cells. Compound 13, as a single drug, suppresses the growth of tumors by a %TGI factor of 60...
January 5, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29303024/bortezomib-in-combination-with-dose-adjusted-epoch-etoposide-prednisone-vincristine-cyclophosphamide-and-doxorubicin-induces-long-term-survival-in-patients-with-plasmablastic-lymphoma-a-retrospective-analysis
#18
Christopher Dittus, Natalie Grover, Steven Ellsworth, Xianming Tan, Steven I Park
Plasmablastic lymphoma (PBL) is a rare and aggressive form of B-cell non-Hodgkin lymphoma. This subtype of lymphoma has a post-germinal center cell-of-origin called the plasmablast, and the immunophenotype is more consistent with that of a plasma cell than a lymphocyte. Because of these unique features, PBL is notoriously difficult to treat. Case reports and small reviews have evaluated the addition of agents directed against plasma cell disorders in combination with traditional lymphoma-directed regimens. We describe the largest case series to date, with the longest follow-up, evaluating bortezomib in combination with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (V-EPOCH) for the treatment of PBL...
January 5, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29302684/autologous-transplantation-for-newly-diagnosed-multiple-myeloma-in-the-era-of-novel-agent-induction-a-systematic-review-and-meta-analysis
#19
Binod Dhakal, Aniko Szabo, Saurabh Chhabra, Mehdi Hamadani, Anita D'Souza, Saad Z Usmani, Rita Sieracki, Bishal Gyawali, Jeffrey L Jackson, Fotis Asimakopoulos, Parameswaran N Hari
Importance: The role of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma continues to be debated in the context of novel agent induction. Objective: To perform a systematic review, conventional meta-analysis, and network meta-analysis of all phase 3 randomized clinical trials (RCTs) evaluating the role of HDT/ASCT. Data Sources: We performed a systematic literature search of Cochrane Central, MEDLINE, and Scopus from January 2000 through April 2017 and relevant annual meeting abstracts from January 2014 to December 2016...
January 4, 2018: JAMA Oncology
https://www.readbyqxmd.com/read/29300929/downregulation-of-skp2-in-papillary-thyroid-cancer-acts-synergistically-with-trail-on-inducing-apoptosis-via-ros
#20
Poyil Pratheeshkumar, Abdul K Siraj, Sasidharan Padmaja Divya, Sandeep Kumar Parvathareddy, Rafia Begum, Roxanne Melosantos, Saif S Al-Sobhi, Mohammed Al-Dawish, Fouad Al-Dayel, Khawla S Al-Kuraya
Context and Objective: S-phase kinase protein 2 (SKP2), is an F-box protein with proteasomal properties and has been found to be overexpressed in a variety of cancers. However, its role in papillary thyroid cancer (PTC) has not been fully elucidated. Experimental Design: SKP2 expression was assessed by immunohistochemistry in a tissue microarray format on a cohort of more than 1000 PTC samples. In vitro and in vivo studies were performed using proteasome inhibitor bortezomib and proapoptopic death ligand TRAIL either alone or combination on PTC cell lines...
December 28, 2017: Journal of Clinical Endocrinology and Metabolism
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