keyword
MENU ▼
Read by QxMD icon Read
search

Abt-199

keyword
https://www.readbyqxmd.com/read/28578655/potential-mechanisms-of-resistance-to-venetoclax-and-strategies-to-circumvent-it
#1
Stephen K Tahir, Morey L Smith, Paul Hessler, Lisa Roberts Rapp, Kenneth B Idler, Chang H Park, Joel D Leverson, Lloyd T Lam
BACKGROUND: Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges...
June 2, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28468776/vulnerability-of-small-cell-lung-cancer-to-apoptosis-induced-by-the-combination-of-bet-bromodomain-proteins-and-bcl2-inhibitors
#2
Lloyd T Lam, Xiaoyu Lin, Emily J Faivre, Ziping Yang, Xiaoli Huang, Denise M Wilcox, Richard J Bellin, Sha Jin, Stephen K Tahir, Michael Mitten, Terry Magoc, Anahita Bhathena, Warren M Kati, Daniel H Albert, Yu Shen, Tamar Uziel
10% to 15% of all lung cancers are small cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis such as MYC, CCND2, and BCL2L1 Here, we demonstrate that ~50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075...
May 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28446281/-effect-of-cdk-inhibitor-ls-007-on-acute-lymphoblastic-leukemia-and-its-mechanism
#3
Jiang-Feng Lu, Feng-Ling Xu, Jun Lu, Yu-Guo Ren
OBJECTIVE: To study the effect of cyclin dependent kinase(CDK) inhibitor LS-007 on acute lymphoblastic leukemia and its mechanism. METHODS: The acute lymphocytic leukemia cell line was cultured and treated by LS-007, flavopiridol and ABT-199, then the changes of apoptosis-related factor mRNA and protein levels were detected by using mRNA quantitative PCR and Werstern blot. RESULTS: quantitative PCR and Western blot detection showed that the levels of antiapoptotic protein decreased significantly in acute lymphoblastic leukemia cells after LS-007 treatment, and the pro-apoptotic effect of LS-007 combined with ABT-199 was much better...
April 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28428442/combination-of-ibrutinib-and-abt-199-in-diffuse-large-b-cell-lymphoma-and-follicular-lymphoma
#4
Hsu-Ping Kuo, Scott A Ezell, Karl J Schweighofer, Leo W K Cheung, Sidney Hsieh, Mutiah Apatira, Mint Sirisawad, Karl Eckert, Ssucheng J Hsu, Chun-Te Chen, Darrin M Beaupre, Matthias Versele, Betty Y Chang
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton tyrosine kinase (BTK)-mediated B-cell receptor signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance...
April 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28398276/bcl-2-as-a-therapeutic-target-in-chronic-lymphocytic-leukemia
#5
REVIEW
Catherine Daniel, Anthony R Mato
Venetoclax (formerly ABT-199) was recently approved in the United States for the treatment of patients who have relapsed or refractory chronic lymphocytic leukemia (CLL) with the 17p deletion. Venetoclax has demonstrated marked activity as monotherapy as well as in combination with cytotoxic chemotherapies, B-cell receptor inhibitors, and anti-CD20 monoclonal antibodies across the spectrum of CLL. The potency of venetoclax has been associated with a unique ability to induce deep (minimal residual disease-negative) complete remissions that appear to be durable...
March 2017: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/28331288/development-of-venetoclax-for-therapy-of-lymphoid-malignancies
#6
REVIEW
Huayuan Zhu, Alexandru Almasan
B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28212732/bcl-2-long-and-winding-path-from-discovery-to-therapeutic-target
#7
REVIEW
Robyn L Schenk, Andreas Strasser, Grant Dewson
In 1988, the BCL-2 protein was found to promote cancer by limiting cell death rather than enhancing proliferation. This discovery set the wheels in motion for an almost 30 year journey involving many international research teams that has recently culminated in the approval for a drug, ABT-199/venetoclax/Venclexta that targets this protein in the treatment of cancer. This review will describe the long and winding path from the discovery of this protein and understanding the fundamental process of apoptosis that BCL-2 and its numerous homologues control, through to its exploitation as a drug target that is set to have significant benefit for cancer patients...
January 15, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28161988/therapeutic-inhibition-of-bcl-2-and-related-family-members
#8
REVIEW
Michelle A Levy, David F Claxton
BCL-2 proteins are key players in the balance of cell life and death. Their roles in the development and biology of cancer have been well established and continue to be investigated. Understanding the mechanisms by which these proteins regulate apoptosis has led to the development of small molecule targeted therapies that act to overcome the cell's ability to evade programmed cell death. Areas covered: The biology of the intrinsic apoptotic pathway is reviewed with attention to the varied roles of the anti-apoptotic members of the BCL-2 family...
March 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28074072/targeting-bet-proteins-improves-the-therapeutic-efficacy-of-bcl-2-inhibition-in-t-cell-acute-lymphoblastic-leukemia
#9
S Peirs, V Frismantas, F Matthijssens, W Van Loocke, T Pieters, N Vandamme, B Lintermans, M P Dobay, G Berx, B Poppe, S Goossens, B C Bornhauser, J-P Bourquin, P Van Vlierberghe
Inhibition of anti-apoptotic BCL-2 has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET bromodomain inhibitor JQ1...
January 11, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28056525/venetoclax-a-first-in-class-oral-bcl-2-inhibitor-for-the-management-of-lymphoid-malignancies
#10
Amber C King, Tim J Peterson, Troy Z Horvat, Mabel Rodriguez, Laura A Tang
OBJECTIVE: To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies. DATA SOURCES: A literature search was performed of PubMed and MEDLINE databases (2005 to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta...
May 2017: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/28043871/bcl-2-inhibitors-reduce-steroid-insensitive-airway-inflammation
#11
Bao-Ping Tian, Li-Xia Xia, Zheng-Qiang Bao, Hao Zhang, Zhi-Wei Xu, Yuan-Yuan Mao, Chao Cao, Luan-Qing Che, Jin-Kai Liu, Wen Li, Zhi-Hua Chen, Songmin Ying, Hua-Hao Shen
BACKGROUND: Asthmatic inflammation is dominated by accumulation of either eosinophils, neutrophils, or both in the airways. Disposal of these inflammatory cells is the key to disease control. Eosinophilic airway inflammation is responsive to corticosteroid treatment, whereas neutrophilic inflammation is resistant and increases the burden of global health care. Corticosteroid-resistant neutrophilic asthma remains mechanistically poorly understood and requires novel effective therapeutic strategies...
December 31, 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28038464/mcl-1-expression-and-jnk-activation-induces-a-threshold-for-apoptosis-in-bcl-xl-overexpressing-hematopoietic-cells
#12
Yu Zhang, Xin Li, Shisheng Tan, Xinyu Liu, Xinyu Zhao, Zhu Yuan, Chunlai Nie
The regulation of Mcl-1 expression is necessary for the induction of cancer cell apoptosis by ABTs such as ABT-737, ABT-263 and ABT-199. However, the reduction in Mcl-1 expression is not sufficient for initiating cell death in hematopoietic cancer cells with high Bcl-xL expression. Here, we demonstrate that 2-deoxyglucose (2-DG) enhanced the effect of ABT-199 to induce cell apoptosis in hematologic malignancies with up-regulated Bcl-xL expression. Our study revealed that 2-DG could decrease glucose-dependent and Akt-independent Mcl-1 expression, which is mediated by the mechanistic target of rapamycin complex 1 (mTORC1) pathway...
February 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28017967/duvelisib-treatment-is-associated-with-altered-expression-of-apoptotic-regulators-that-helps-in-sensitization-of-chronic-lymphocytic-leukemia-cells-to-venetoclax-abt-199
#13
V M Patel, K Balakrishnan, M Douglas, T Tibbitts, E Y Xu, J L Kutok, M Ayers, A Sarkar, R Guerrieri, W G Wierda, S O'Brien, N Jain, H M Stern, V Gandhi
Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes...
February 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27994761/gossypol-with-hydrophobic-linear-esters-exhibits-enhanced-antitumor-activity-as-an-inhibitor-of-antiapoptotic-proteins
#14
Yuzhi Lu, Shuangchan Wu, Yuan Yue, Si He, Jun Li, Jun Tang, Wei Wang, Hai-Bing Zhou
A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups. The optimized products showed low micromolar pan antitumor activities against NCI-60 tumor cell lines, which is promising for further drug development...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27993930/metabolism-and-disposition-of-a-novel-b-cell-lymphoma-2-inhibitor-venetoclax-in-humans-and-characterization-of-its-unusual-metabolites
#15
Hong Liu, Melissa J Michmerhuizen, Yanbin Lao, Katty Wan, Ahmed Hamed Salem, James Sawicki, Michael Serby, Srirajan Vaidyanathan, Shekman L Wong, Suresh Agarwal, Martin Dunbar, Jens Sydor, Sonia M de Morais, Anthony J Lee
Venetoclax (ABT-199), a B-cell lymphoma-2 (Bcl-2) protein inhibitor, is currently in clinical development for the treatment of hematologic malignancies. We characterized the absorption, metabolism, and excretion of venetoclax in humans. After a single oral dose of [(14)C]venetoclax to healthy volunteers, the recovery of total radioactive dose was 100%, with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0.1%). The extent of absorption was estimated to be at least 65%...
March 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27913204/the-selective-bcl-2-inhibitor-venetoclax-a-bh3-mimetic-does-not-dysregulate-intracellular-ca-2-signaling
#16
Tamara Vervloessem, Hristina Ivanova, Tomas Luyten, Jan B Parys, Geert Bultynck
Anti-apoptotic B cell-lymphoma-2 (Bcl-2) proteins are emerging as therapeutic targets in a variety of cancers for precision medicines, like the BH3-mimetic drug venetoclax (ABT-199), which antagonizes the hydrophobic cleft of Bcl-2. However, the impact of venetoclax on intracellular Ca(2+) homeostasis and dynamics in cell systems has not been characterized in detail. Here, we show that venetoclax did not affect Ca(2+)-transport systems from the endoplasmic reticulum (ER) in permeabilized cell systems. Venetoclax (1μM) did neither trigger Ca(2+) release by itself nor affect agonist-induced Ca(2+) release in a variety of intact cell models...
November 30, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27907031/in-vitro-pre-clinical-validation-of-suicide-gene-modified-anti-cd33-redirected-chimeric-antigen-receptor-t-cells-for-acute-myeloid-leukemia
#17
Kentaro Minagawa, Muhammad O Jamil, Mustafa Al-Obaidi, Larisa Pereboeva, Donna Salzman, Harry P Erba, Lawrence S Lamb, Ravi Bhatia, Shin Mineishi, Antonio Di Stasi
BACKGROUND: Approximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematopoietic stem cell transplant for high-risk patients. Despite allogeneic hematopoietic stem cell transplant about 25% of patients still succumb to disease relapse, therefore, novel strategies are needed to improve the outcome of patients with acute myeloid leukemia...
2016: PloS One
https://www.readbyqxmd.com/read/27806433/targeting-bcl2-with-bh3-mimetics-basic-science-and-clinical-application-of-venetoclax-in-chronic-lymphocytic-leukemia-and-related-b-cell-malignancies
#18
REVIEW
A W Roberts, Dcs Huang
The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed...
January 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27725868/synergistic-anti-leukemic-interactions-between-abt-199-and-panobinostat-in-acute-myeloid-leukemia-ex-vivo
#19
Jonathan Schwartz, Xiaojia Niu, Eric Walton, Laura Hurley, Hai Lin, Holly Edwards, Jeffrey W Taub, Zhihong Wang, Yubin Ge
Cure rates for acute myeloid leukemia (AML) remain suboptimal; thus new treatment strategies are needed for this deadly disease. Poor clinical outcomes have been associated with overexpression of the anti-apoptotic Bcl-2 family proteins Bcl-2, Bcl-xL, and Mcl-1, which have garnered great interest as therapeutic targets. While the Bcl-2-selective inhibitor ABT-199 has demonstrated promising preclinical anti-leukemic activities, intrinsic drug resistance remains a problem. In our most recent study, we identified Mcl-1 sequestration of Bim as a mechanism of intrinsic resistance to ABT-199 in AML cells, thus upregulating Bim could overcome such resistance...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27722045/bcl-2-inhibition-impairs-mitochondrial-function-and-targets-oral-tongue-squamous-cell-carcinoma
#20
Lei Xiong, Yi Tang, Zhaoyang Liu, Jing Dai, Xiaozhou Wang
PURPOSE: To understand the role of Bcl-2 overexpression in oral tongue squamous cell carcinoma (OTSCC) patients and investigate the efficacy of targeting Bcl-2 in OTSCC. METHODS: The expression level of Bcl-2 on normal tongue cells and OTSCC cells were measured by real-time PCR and western blotting. The functional roles of Bcl-2 were examined by MTS, flow cytometry and xenograft cancer mouse model. Mechanism studies were performed by analyzing mitochondrial functions in a panel of OTSCC cell lines...
2016: SpringerPlus
keyword
keyword
20327
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"