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https://www.readbyqxmd.com/read/29768700/cell-and-tissue-based-proteome-profiling-and-dual-imaging-of-apoptosis-markers-with-probes-derived-from-venetoclax-and-idasanutlin
#1
Zhengqiu Li, Dongsheng Zhu, Haijun Guo, Yu Chang, Yun Ni, Lin Li, Piliang Hao, Yong Xu, Ke Ding
Venetoclax (ABT-199) and idasanutlin (RG7388) are efficient anticancer drugs targeting two essential apoptosis markers, Bcl2 and MDM2, respectively. Recent studies have shown that the combination of these two drugs leads to remarkable enhancement of anticancer efficacy, both in vitro and in vivo. In an attempt to understand the mechanism of this synergistic effect, competitive affinity-based proteome profiling coupled with bioimaging was employed to characterize their protein targets in the same cancer cell line and tumor tissue...
May 16, 2018: Angewandte Chemie
https://www.readbyqxmd.com/read/29767411/mek1-2-inhibition-by-binimetinib-is-effective-as-a-single-agent-and-potentiates-the-actions-of-venetoclax-and-abt-737-under-conditions-that-mimic-the-chronic-lymphocytic-leukaemia-cll-tumour-microenvironment
#2
Kyle Crassini, Yandong Shen, William S Stevenson, Richard Christopherson, Chris Ward, Stephen P Mulligan, O Giles Best
The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma-conditioned media and phorbol myristylate (PMA)...
May 16, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29761903/the-combination-of-a-sphingosine-kinase-2-inhibitor-abc294640-and-a-bcl-2-inhibitor-abt-199-displays-synergistic-anti-myeloma-effects-in-myeloma-cells-without-a-t-11-14-translocation
#3
Pasupathi Sundaramoorthy, Cristina Gasparetto, Yubin Kang
Multiple myeloma (MM) remains an incurable disease in need of the development of novel therapeutic agents and drug combinations. ABT-199 is a specific Bcl-2 inhibitor in clinical trials for MM; however, its activity as a single agent was limited to myeloma patients with the t(11;14) translocation who acquire resistance due to co-expression of Mcl-1 and Bcl-xL. These limitations preclude its use in a broader patient population. We have recently found that a sphingosine kinase 2-specific inhibitor (ABC294640) induces apoptosis in primary human CD138+ cells and MM cell lines...
May 15, 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29757239/preparation-physicochemical-and-antioxidant-properties-of-acid-and-pepsin-soluble-collagens-from-the-swim-bladders-of-miiuy-croaker-miichthys-miiuy
#4
Wen-Hao Zhao, Chang-Feng Chi, Yu-Qin Zhao, Bin Wang
Collagen is one of the most useful biomaterials and widely applied in functional food and cosmetics. However, some consumers have paid close attention to the safety of mammalian collagens because of the outbreaks of bovine spongiform encephalopathy (BSE), foot-and-mouth disease (FMD), and other prion diseases. Therefore, there is a strong demand for developing alternative sources of collagen, with one promising source being from the process by-products of commercial fisheries. In this report, acid-soluble collagen (ASC-SB) and pepsin-soluble collagen (PSC-SB) from swim bladders of miiuy croaker ( Miichthys miiuy ) were isolated with yields of 1...
May 12, 2018: Marine Drugs
https://www.readbyqxmd.com/read/29748439/autologous-t-cell-activation-fosters-abt-199-resistance-in-chronic-lymphocytic-leukemia-rationale-for-a-combined-therapy-with-syk-inhibitors-and-anti-cd20-moabs
#5
Esteban Enrique Elías, María Belén Almejún, Ana Colado, Gregorio Cordini, Maricef Vergara-Rubio, Enrique Podaza, Denise Risnik, María Cabrejo, Horacio Fernández-Grecco, Raimundo Fernando Bezares, María Del Rosario Custidiano, Julio César Sánchez-Ávalos, Ángeles Vicente, Gonzalo Martín Garate, Mercedes Borge, Mirta Giordano, Romina Gamberale
No abstract text is available yet for this article.
May 10, 2018: Haematologica
https://www.readbyqxmd.com/read/29732004/s55746-is-a-novel-orally-active-bcl-2-selective-and-potent-inhibitor-that-impairs-hematological-tumor-growth
#6
Patrick Casara, James Davidson, Audrey Claperon, Gaëtane Le Toumelin-Braizat, Meike Vogler, Alain Bruno, Maïa Chanrion, Gaëlle Lysiak-Auvity, Thierry Le Diguarher, Jérôme-Benoît Starck, Ijen Chen, Neil Whitehead, Christopher Graham, Natalia Matassova, Pawel Dokurno, Christopher Pedder, Youzhen Wang, Shumei Qiu, Anne-Marie Girard, Emilie Schneider, Fabienne Gravé, Aurélie Studeny, Ghislaine Guasconi, Francesca Rocchetti, Sophie Maïga, Jean-Michel Henlin, Frédéric Colland, Laurence Kraus-Berthier, Steven Le Gouill, Martin J S Dyer, Roderick Hubbard, Mike Wood, Martine Amiot, Gerald M Cohen, John A Hickman, Erick Morris, James Murray, Olivier Geneste
Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29707107/selective-inhibition-of-bcl-2-is-a-promising-target-in-patients-with-high-risk-myelodysplastic-syndromes-and-adverse-mutational-profile
#7
Veronika Reidel, Johanna Kauschinger, Richard T Hauch, Catharina Müller-Thomas, Niroshan Nadarajah, Rainer Burgkart, Burkhard Schmidt, Dirk Hempel, Anne Jacob, Julia Slotta-Huspenina, Ulrike Höckendorf, Christian Peschel, Wolfgang Kern, Torsten Haferlach, Katharina S Götze, Stefanie Jilg, Philipp J Jost
Somatic mutations in genes such as ASXL1 , RUNX1 , TP53 or EZH2 adversely affect the outcome of patients with myelodysplastic syndromes (MDS). Since selective BCL-2 inhibition is a promising treatment strategy in hematologic malignancies, we tested the therapeutic impact of ABT-199 on MDS patient samples bearing an adverse mutational profile. By gene expression, we found that the level of pro-apoptotic BIM significantly decreased during MDS disease progression in line with an acquired resistance to cell death...
April 3, 2018: Oncotarget
https://www.readbyqxmd.com/read/29477371/venetoclax-a-new-wave-in-hematooncology
#8
REVIEW
Jana Mihalyova, Tomas Jelinek, Katerina Growkova, Matous Hrdinka, Michal Simicek, Roman Hajek
Inhibitors of antiapoptotic proteins of the BCL2 family can successfully restart the deregulated process of apoptosis in malignant cells. Whereas nonselective agents have been limited by their affinity to different BCL2 members, thus inducing excessive toxicity, the highly selective BCL2 inhibitor venetoclax (ABT-199, Venclexta™) has an acceptable safety profile. To date, it has been approved in monotherapy for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion. Extension of indications can be expected in monotherapy and in combination regimens...
May 2018: Experimental Hematology
https://www.readbyqxmd.com/read/29459573/potential-role-of-asc-a-proapoptotic-protein-for-determining-the-cisplatin-susceptibility-of-lung-cancer-cells
#9
Takao Sakaizawa, Tomio Matsumura, Chifumi Fujii, Shigeaki Hida, Masayuki Toishi, Takayuki Shiina, Kazuo Yoshida, Kazutoshi Hamanaka, Ken-Ichi Ito, Shun'ichiro Taniguchi
Primary lung cancer is the most frequent cause of cancer-related deaths worldwide. Cisplatin has been used as a key drug in the treatment for patients with lung cancer; however, most of the patients failed to respond to cisplatin within several months, and the mechanisms underlying the cisplatin resistance have not been fully elucidated. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein in the formation of inflammasomes. ASC is also involved in apoptotic signaling...
February 2018: Tohoku Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29441961/clinically-relevant-interactions-of-anti-apoptotic-bcl-2-protein-inhibitors-with-abc-transporters
#10
E Ruzickova, R Janska, P Dolezel, P Mlejnek
In this work we studied clinically relevant interactions between the BH3 mimetics and the ABCB1 and ABCG2 transporters. We observed that the intracellular levels of ABT-263 and ABT-199, but not ABT-737, might be reduced by ABCB1 or ABCG2. Importantly, this effect was proportional to the transporter expression level. High transporter expression levels decreased the intracellular levels of ABT-263 and ABT-199 substantially. Low transporter expression levels, which are clinically relevant, affected the intracellular level of ABT-263 slightly but significantly, however, they failed to decrease the intracellular level of ABT-199 below the control level in parental cells...
December 1, 2017: Die Pharmazie
https://www.readbyqxmd.com/read/29431553/quantitative-assessment-of-the-sensitivity-of-dormant-aml-cells-to-the-bad-mimetics-abt-199-and-abt-737
#11
Ning Yu, Claire Seedhouse, Nigel Russell, Monica Pallis
Cells from patients with acute myeloid leukemia (AML) that remain dormant and protected by stromal cells may escape effects of chemotherapy. We modeled dormancy in vitro and investigated the ability of Bcl-2 inhibitors ABT-199 and ABT-737 to overcome chemoprotection of dormant cells. CD34-enriched primary AML cells with aberrant leukemia-associated phenotypes (LAPs) were cultured on stromal cells. The chemosensitivity of dormant (PKH26high ), CD34+, LAP+ cells was ascertained by 5-colour flow cytometric counting after 12 d...
February 12, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29407973/small-molecule-mcl-1-inhibitors-emerging-anti-tumor-agents
#12
Yichao Wan, Ningning Dai, Zilong Tang, Hao Fang
The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members...
February 25, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29353886/the-bet-bromodomain-inhibitor-cpi203-overcomes-resistance-to-abt-199-venetoclax-by-downregulation-of-bfl-1-a1-in-in-vitro-and-in-vivo-models-of-myc-bcl2-double-hit-lymphoma
#13
A Esteve-Arenys, J G Valero, A Chamorro-Jorganes, D Gonzalez, V Rodriguez, I Dlouhy, I Salaverria, E Campo, D Colomer, A Martinez, G Rymkiewicz, P Pérez-Galán, A Lopez-Guillermo, G Roué
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, mostly known as double-hit lymphoma (DHL), is a rare entity characterized by morphologic and molecular features between Burkitt lymphoma and the clinically manageable diffuse large B-cell lymphoma (DLBCL). DHL patients usually undergo a rapidly progressing clinical course associated with resistance to standard chemo-immunotherapy. As a consequence, the prognosis of this entity is particularly poor with a median overall survival inferior to 1 year...
April 2018: Oncogene
https://www.readbyqxmd.com/read/29340082/reciprocal-sensitivity-of-diffuse-large-b-cell-lymphoma-cells-to-bcl-2-inhibitors-bird-2-versus-venetoclax
#14
Tamara Vervloessem, Haidar Akl, Thomas Tousseyn, Humbert De Smedt, Jan B Parys, Geert Bultynck
Bcl-2 is often upregulated in cancers to neutralize the BH3-only protein Bim at the mitochondria. BH3 mimetics (e.g. ABT-199 (venetoclax)) kill cancer cells by targeting Bcl-2's hydrophobic cleft and disrupting Bcl-2/Bim complexes. Some cancers with elevated Bcl-2 display poor responses towards BH3 mimetics, suggesting an additional function for anti-apoptotic Bcl-2 in these cancers. Indeed, Bcl-2 via its BH4 domain prevents cytotoxic Ca2+ release from the endoplasmic reticulum (ER) by directly inhibiting the inositol 1,4,5-trisphosphate receptor (IP3 R)...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29298347/predicting-effective-pro-apoptotic-anti-leukaemic-drug-combinations-using-co-operative-dynamic-bh3-profiling
#15
Martin Grundy, Claire Seedhouse, Thomas Jones, Liban Elmi, Michael Hall, Adam Graham, Nigel Russell, Monica Pallis
The BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-leukaemic drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism using the technique of dynamic BH3 profiling, whereby cells were primed with drugs to discover whether this would elicit mitochondrial outer membrane permeabilisation in response to BCL-2-targeting BAD-BH3 peptide or MCL-1-targeting MS1-BH3 peptide...
2018: PloS One
https://www.readbyqxmd.com/read/29241222/flavopiridol-enhances-abt-199-sensitivity-in-unfavourable-risk-multiple-myeloma-cells-in-vitro-and-in-vivo
#16
Liang Zhou, Yu Zhang, Deepak Sampath, Joel Leverson, Yun Dai, Maciej Kmieciak, Matthew Nguyen, Robert Z Orlowski, Steven Grant
BACKGROUND: The BCL-2-specific BH3-mimetic ABT-199 (venetoclax) has been reported to be principally active against favourable-risk multiple myeloma (MM) cells, prompting efforts to extend its activity to include more resistant, higher-risk MM subsets. METHODS: Effects of the CDK9 inhibitor flavopiridol (FP; alvocidib) on responses to ABT-199 were examined in MM cells. Cell death and protein expression were evaluated by western blot and immunofluorescence. Xenograft models were used to study combination effects in vivo...
February 6, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29208365/targeting-pi3k-mtor-erk-and-bcl-2-signaling-network-shows-superior-antileukemic-activity-against-aml-ex-vivo
#17
Yongwei Su, Xinyu Li, Jun Ma, Jianyun Zhao, Shuang Liu, Guan Wang, Holly Edwards, Jeffrey W Taub, Hai Lin, Yubin Ge
Acute myeloid leukemia (AML) remains challenging to treat and needs more effective treatments. The PI3K/mTOR pathway is involved in cell survival and has been shown to be constitutively active in 50-80% of AML patients. However, targeting the PI3K/mTOR pathway results in activation of the ERK pathway, which also plays an important role in cell survival. In addition, AML cells often overexpress antiapoptotic Bcl-2 family proteins (e.g., Bcl-2), preventing cell death. Thus, our strategy here is to target the PI3K, mTOR (by VS-5584, a PI3K and mTOR dual inhibitor), ERK (by SCH772984, an ERK-selective inhibitor), and Bcl-2 (by ABT-199, a Bcl-2-selective inhibitor) signaling network to kill AML cells...
February 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29197725/exploring-the-selectivity-of-inhibitor-complexes-with-bcl-2-and-bcl-xl-a-molecular-dynamics-simulation-approach
#18
Naoki Wakui, Ryunosuke Yoshino, Nobuaki Yasuo, Masahito Ohue, Masakazu Sekijima
B-cell lymphoma 2 (Bcl-2) family proteins are potential drug targets in cancer and have a relatively flat and flexible binding site. ABT-199 is one of the most promising selective Bcl-2 inhibitors, and A-1155463 selectively inhibits Bcl-XL. Although the amino acid sequences of the binding sites of these two inhibitors are similar, the inhibitors selectively bind the target protein. In order to determine the origin of the selectivity of these inhibitors, we conducted molecular dynamics simulations using protein-inhibitor modeling...
January 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29163807/macitentan-a-double-antagonist-of-endothelin-receptors-efficiently-impairs-migration-and-microenvironmental-survival-signals-in-chronic-lymphocytic-leukemia
#19
Rossana Maffei, Stefania Fiorcari, Tiziana Vaisitti, Silvia Martinelli, Stefania Benatti, Giulia Debbia, Davide Rossi, Patrizia Zucchini, Leonardo Potenza, Mario Luppi, Gianluca Gaidano, Silvia Deaglio, Roberto Marasca
The crosstalk between chronic lymphocytic leukemia (CLL) cells and tumor microenvironment is essential for leukemic clone maintenance, supporting CLL cells survival, proliferation and protection from drug-induced apoptosis. Over the past years, the role of several soluble factors involved in these processes has been studied. CLL cells express higher levels of endothelin 1 (ET-1) and ETA receptor as compared to normal B cells. Upon ET-1 stimulation, CLL cells improve their survival and proliferation and reduce their sensitivity to the phosphoinositide-3-kinase δ inhibitor idelalisib and to fludarabine...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29099483/the-bcl-2-arbiters-of-apoptosis-and-their-growing-role-as-cancer-targets
#20
REVIEW
Jerry M Adams, Suzanne Cory
Impaired apoptosis plays a central role in cancer development and limits the efficacy of conventional cytotoxic therapies. Deepening understanding of how opposing factions of the BCL-2 protein family switch on apoptosis and of their structures has driven development of a new class of cancer drugs that targets various pro-survival members by mimicking their natural inhibitors, the BH3-only proteins. These 'BH3 mimetic' drugs seem destined to become powerful new weapons in the arsenal against cancer. Successful clinical trials of venetoclax/ABT-199, a specific inhibitor of BCL-2, have led to its approval for a refractory form of chronic lymphocytic leukaemia and to scores of on-going trials for other malignancies...
January 2018: Cell Death and Differentiation
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