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Abt-199

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https://www.readbyqxmd.com/read/29241222/flavopiridol-enhances-abt-199-sensitivity-in-unfavourable-risk-multiple-myeloma-cells-in-vitro-and-in-vivo
#1
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...
December 14, 2017: 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
#2
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...
December 2, 2017: 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
#3
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...
November 23, 2017: 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
#4
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
#5
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...
November 3, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29061914/therapeutics-targeting-bcl-2-in-hematological-malignancies
#6
REVIEW
Astrid Ruefli-Brasse, John C Reed
Members of the B-cell lymphoma 2 (BCL-2) gene family are attractive targets for cancer therapy as they play a key role in promoting cell survival, a long-since established hallmark of cancer. Clinical utility for selective inhibition of specific anti-apoptotic Bcl-2 family proteins has recently been realized with the Food and Drug Administration (FDA) approval of venetoclax (formerly ABT-199/GDC-0199) in relapsed chronic lymphocytic leukemia (CLL) with 17p deletion. Despite the impressive monotherapy activity in CLL, such responses have rarely been observed in other B-cell malignancies, and preclinical data suggest that combination therapies will be needed in other indications...
October 23, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29016820/selective-bcl-xl-inhibition-promotes-apoptosis-in-combination-with-mln8237-in-medulloblastoma-and-pediatric-glioblastoma-cells
#7
Jane Levesley, Lynette Steele, Anke Brüning-Richardson, Adam Davison, Jia Zhou, Chunyong Ding, Sean Lawler, Susan C Short
Background: CNS tumors, including medulloblastoma and pediatric glioblastoma (pGBM) account for the majority of solid pediatric malignancies. There remains an unmet need to identify novel treatment approaches in poor prognosis and relapsed pediatric brain tumors, where therapeutic options are limited. Small-molecule B-cell lymphoma 2 (BCL-2) family inhibitors may enhance tumor cell killing when combined with conventional and targeted chemotherapeutic agents. We investigated the effect of disrupting BCL-2 and B cell lymphoma-extra large (BCL-XL) protein function using ABT-263, ABT-199 and WEHI-539 in medulloblastoma and pGBM cells following treatment with MLN8237, an Aurora kinase inhibitor under investigation as a novel agent for the treatment of malignant brain tumors...
July 20, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28984869/bcl2-and-mir-15-16-from-gene-discovery-to-treatment
#8
REVIEW
Yuri Pekarsky, Veronica Balatti, Carlo M Croce
In 1984, we investigated the t(14;18) chromosomal translocations that frequently occur in patients with follicular lymphoma. We first identified a locus on chromosome 18 involved in these translocations with the chromosome 14 containing the immunoglobulin heavy chain locus. Within this region on chromosome 18, we then discovered a gene that we called BCL2, which was activated by the translocations. Since that time, many studies determined that BCL2 is one of the most important oncogenes involved in cancer by inhibiting apoptosis...
October 6, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28972014/first-in-human-response-of-bcl-2-inhibitor-venetoclax-in-t-cell-prolymphocytic-leukemia
#9
Bernd Boidol, Christoph Kornauth, Emiel van der Kouwe, Nicole Prutsch, Lukas Kazianka, Sinan Gültekin, Gregor Hoermann, Marius E Mayerhoefer, Georg Hopfinger, Alexander Hauswirth, Michael Panny, Marie-Bernadette Aretin, Bernadette Hilgarth, Wolfgang R Sperr, Peter Valent, Ingrid Simonitsch-Klupp, Richard Moriggl, Olaf Merkel, Lukas Kenner, Ulrich Jäger, Stefan Kubicek, Philipp B Staber
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with a short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 FDA-approved anti-cancer drugs or compounds currently in clinical development we pursued to identify novel effective treatments for T-PLL patients. We found that the BCL-2 inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL specific response when comparing individual ex vivo drug response in 86 patients with refractory hematologic malignancies...
September 27, 2017: Blood
https://www.readbyqxmd.com/read/28947136/bcl-xl-selective-bh3-mimetic-sensitizes-rhabdomyosarcoma-cells-to-chemotherapeutics-by-activation-of-the-mitochondrial-pathway-of-apoptosis
#10
Sara Fatima Faqar-Uz-Zaman, Ulrike Heinicke, Michael Torsten Meister, Meike Vogler, Simone Fulda
BH3 mimetics are a promising new class of anticancer agents that inhibit antiapoptotic BCL-2 proteins. Here, we report that BH3 mimetics selectively targeting BCL-xL, BCL-2 or MCL-1 (i.e. A-1331852, ABT-199, A-1210477) act in concert with multiple chemotherapeutic agents (i.e. vincristine (VCR), etoposide (ETO), doxorubicin, actinomycin D and cyclophosphamide) to induce apoptosis in rhabdomyosarcoma (RMS) cells. Similarly, genetic knockdown of BCL-xL primes RMS cells to VCR- or ETO-induced cell death, highlighting the importance of BCL-xL in mediating chemotherapy resistance in RMS...
September 23, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28915653/dual-targeting-of-mdm2-and-bcl2-as-a-therapeutic-strategy-in-neuroblastoma
#11
Alan Van Goethem, Nurten Yigit, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Eveline Barbieri, Frank Speleman, Jason Shohet, Jo Vandesompele, Tom Van Maerken
Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28852199/mutant-jak3-phosphoproteomic-profiling-predicts-synergism-between-jak3-inhibitors-and-mek-bcl2-inhibitors-for-the-treatment-of-t-cell-acute-lymphoblastic-leukemia
#12
S Degryse, C E de Bock, S Demeyer, I Govaerts, S Bornschein, D Verbeke, K Jacobs, S Binos, D A Skerrett-Byrne, H C Murray, N M Verrills, P Van Vlierberghe, J Cools, M D Dun
Mutations in the interleukin-7 receptor (IL7R) or the JAK3 kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here, we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib...
August 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28838268/rational-combination-strategies-to-enhance-venetoclax-activity-and-overcome-resistance-in-hematologic-malignancies
#13
Steven Grant
Venetoclax (ABT-199) is a Bcl-2-specific BH3-mimetic that has shown significant promise in certain subtypes of CLL as well as in several other hematologic malignancies. As in the case of essentially all targeted agents, intrinsic or acquired resistance to this agent generally occurs, prompting the search for new strategies capable of circumventing this problem. A logical approach to this challenge involves rational combination strategies designed to disable preexisting or induced compensatory survival pathways...
August 24, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28799432/targeted-therapies-in-acute-myeloid-leukemia-a-focus-on-flt-3-inhibitors-and-abt199
#14
REVIEW
Kiran Naqvi, Marina Konopleva, Farhad Ravandi
Acute myeloid leukemia (AML) remains a therapeutic challenge. Despite ongoing research, the standard therapy for AML has not changed significantly in the past four decades. With the identification of cytogenetic and molecular abnormalities, several promising therapeutic agents are currently being investigated. FLT3 mutation is a well-recognized target seen in 30% of the cytogenetically normal AML. More recently, the BCL2 family of anti-apoptotic proteins have also generated great interest as a therapeutic target...
October 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28750570/identification-of-potential-ibrutinib-combinations-in-hematological-malignancies-using-a-combination-high-throughput-screen
#15
Michael Schaffer, Shalini Chaturvedi, Cuc Davis, Regina Aquino, Emily Stepanchick, Matthias Versele, Yang Liu, Jennifer Yang, Rongzhen Lu, Sriram Balasubramanian
Matrix high-throughput screening (HTS) methods are increasingly employed to rapidly define potential therapeutic drug combinations. We used combination HTS to identify compounds showing synergistic anti-proliferative activity with ibrutinib, an irreversible, small-molecule inhibitor of Bruton's tyrosine kinase. The goal was to identify ibrutinib combinations with maximum synergistic effects in heme malignancy lines, particularly in non-Hodgkin lymphoma including diffuse large B-cell lymphoma (DLBCL). Growth inhibition (GI) was used to measure cell viability; synergy scores characterized strength of synergistic interaction...
July 28, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28741496/targeting-bcl-2-like-proteins-to-kill-cancer-cells
#16
REVIEW
Suzanne Cory, Andrew W Roberts, Peter M Colman, Jerry M Adams
Mutations that impair apoptosis contribute to cancer development and reduce the effectiveness of conventional anti-cancer therapies. These insights and understanding of how the B cell lymphoma (BCL)-2 protein family governs apoptosis have galvanized the search for a new class of cancer drugs that target its pro-survival members by mimicking their natural antagonists, the BCL-2 homology (BH)3-only proteins. Successful initial clinical trials of the BH3 mimetic venetoclax/ABT-199, specific for BCL-2, have led to its recent licensing for refractory chronic lymphocytic leukemia and to multiple ongoing trials for other malignancies...
August 2016: Trends in Cancer
https://www.readbyqxmd.com/read/28738256/p53-and-mitf-bcl-2-identified-as-key-pathways-in-the-acquired-resistance-of-nras-mutant-melanoma-to-mek-inhibition
#17
Ahmad Najem, Mohammad Krayem, François Salès, Nader Hussein, Bassam Badran, Caroline Robert, Ahmad Awada, Fabrice Journe, Ghanem E Ghanem
Activating mutations in Neuroblastoma RAS viral oncogene homolog (NRAS) are found in 15-30% of melanomas and are associated with a poor prognosis. Although MAP kinase kinase (MEK) inhibitors used as single agents showed a limited clinical benefit in patients with NRAS-mutant melanoma due to their rather cytostatic effect and high toxicity, their combination with other inhibitors of pathways known to cooperate with MEK inhibition may maximise their antitumour activity. Similarly, in a context where p53 is largely inactivated in melanoma, hyperexpression of Microphthalmia associated transcription factor (MITF) and its downstream anti-apoptotic targets may be the cause of the restraint cytotoxic effects of MEK inhibitors...
September 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28723622/dual-targeting-of-mdm2-and-bcl2-as-a-therapeutic-strategy-in-neuroblastoma
#18
Alan Van Goethem, Nurten Yigit, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Eveline Barbieri, Frank Speleman, Jason Shohet, Jo Vandesompele, Tom Van Maerken
Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28714472/targeting-the-differential-addiction-to-anti-apoptotic-bcl-2-family-for-cancer-therapy
#19
Akane Inoue-Yamauchi, Paul S Jeng, Kwanghee Kim, Hui-Chen Chen, Song Han, Yogesh Tengarai Ganesan, Kota Ishizawa, Sylvia Jebiwott, Yiyu Dong, Maria C Pietanza, Matthew D Hellmann, Mark G Kris, James J Hsieh, Emily H Cheng
BCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263...
July 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28712306/targeting-intrinsic-apoptosis-and-other-forms-of-cell-death-by-bh3-mimetics-in-glioblastoma
#20
REVIEW
Georg Karpel-Massler, Chiaki Tsuge Ishida, Yiru Zhang, Marc-Eric Halatsch, M-Andrew Westhoff, Markus D Siegelin
Novel approaches to treat malignant brain tumors are necessary since these neoplasms still display an unfavorable prognosis. Areas covered: In this review, the authors summarize and analyze recent preclinical data that suggest that targeting intrinsic apoptosis may be a suitable strategy for the treatment of malignant gliomas. They focus on the anti-apoptotic Bcl-2 family members of proteins and the recent drug developments in that field with a special focus on BH3-mimetics. With the discovery of BH3-mimetics that interfere with anti-apoptotic Bcl-2 family members in the low nanomolar range significant excitement has been generated towards these class of inhibitors, such as ABT-737, ABT-263 and the most recent successor, ABT-199 which is most advanced with respect to clinical application...
October 2017: Expert Opinion on Drug Discovery
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