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BH3 mimetics

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https://www.readbyqxmd.com/read/29017053/apoptosis-up-the-ante
#1
Palaniraja Thandapani, Iannis Aifantis
The clinical success of the BH3-mimetic venetoclax has generated increasing interest to target BCL2 family proteins in oncology. In this issue of Cancer Cell, Reyna and colleagues demonstrate the potential of a pharmacological activator of the pro-apoptotic protein BAX to suppress acute myeloid leukemia both alone and together with venetoclax.
October 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28974549/modulation-of-navitoclax-sensitivity-by-dihydroartemisinin-mediated-mcl-1-repression-in-bcr-abl-b-lineage-acute-lymphoblastic-leukemia
#2
Amit Budhraja, Meghan E Turnis, Michelle L Churchman, Anisha Kothari, Xue Yang, Haiyan Xu, Ewa Kaminska, John C Panetta, David Finkelstein, Charles G Mullighan, Joseph T Opferman
PURPOSE: BCR-ABL+ B-ALL leukemic cells are highly dependent on the expression of endogenous anti-apoptotic MCL-1 to promote viability and are resistant to BH3-mimetic agents such as navitoclax (ABT-263) that targets BCL-2, BCL-XL, and BCL-W. However, the survival of most normal blood cells and other cell types are also dependent on Mcl-1. Despite the requirement for MCL-1 in these cell types, initial reports of MCL-1-specific BH3-mimetics have not described any overt toxicities associated with single-agent use, but these agents are still early in clinical development...
October 3, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28960207/bh3-mimetics-efficiently-induce-apoptosis-in-mouse-basophils-and-mast-cells
#3
Ramona Reinhart, Lionel Rohner, Simone Wicki, Michaela Fux, Thomas Kaufmann
Basophil granulocytes and mast cells are recognized for their roles in immunity and are central effectors of diverse immunological disorders. Despite their similarities, there is emerging evidence for non-redundant roles of the circulating yet scarce basophils and tissue-resident mast cells, respectively. Because of their importance in allergic pathogenesis, specific induction of apoptosis in basophils and mast cells may represent an interesting novel treatment strategy. The pro-inflammatory cytokine interleukin-3 serves as a key factor for basophil and mouse mast cell survival...
September 29, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28947954/bh3-mimetic-obatoclax-gx15-070-mediates-mitochondrial-stress-predominantly-via-mcl-1-inhibition-and-induces-autophagy-dependent-necroptosis-in-human-oral-cancer-cells
#4
Prasad Sulkshane, Tanuja Teni
We have previously reported overexpression of antiapoptotic MCL-1 protein in human oral cancers and its association with therapy resistance and poor prognosis, implying it to be a potential therapeutic target. Hence, we investigated the efficacy and mechanism of action of Obatoclax, a BH3 mimetic pan BCL-2 inhibitor in human oral cancer cell lines. All cell lines exhibited high sensitivity to Obatoclax with complete clonogenic inhibition at 200-400 nM concentration which correlated with their MCL-1 expression...
September 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28947136/bcl-xl-selective-bh3-mimetic-sensitizes-rhabdomyosarcoma-cells-to-chemotherapeutics-by-activation-of-the-mitochondrial-pathway-of-apoptosis
#5
Sara Fatima Faqar-Uz-Zaman, Ulrike Heinicke, Michael 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/28945232/extra-mitochondrial-prosurvival-bcl-2-proteins-regulate-gene-transcription-by-inhibiting-the-sufu%C3%A2-tumour-suppressor
#6
Xiaofeng Wu, Li-Shu Zhang, Jason Toombs, Yi-Chun Kuo, John Tyler Piazza, Rubina Tuladhar, Quinn Barrett, Chih-Wei Fan, Xuewu Zhang, Loren D Walensky, Marcel Kool, Steven Y Cheng, Rolf Brekken, Joseph T Opferman, Douglas R Green, Tudor Moldoveanu, Lawrence Lum
Direct interactions between pro- and anti-apoptotic BCL-2 family members form the basis of cell death decision-making at the outer mitochondrial membrane (OMM). Here we report that three anti-apoptotic BCL-2 proteins (MCL-1, BCL-2 and BCL-XL) found untethered from the OMM function as transcriptional regulators of a prosurvival and growth program. Anti-apoptotic BCL-2 proteins engage a BCL-2 homology (BH) domain sequence found in SUFU (suppressor of fused), a tumour suppressor and antagonist of the GLI DNA-binding proteins...
October 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28938651/positive-transcription-elongation-factor-b-p-tefb-is-a-therapeutic-target-in-human-multiple-myeloma
#7
Yu Zhang, Liang Zhou, Yun Leng, Yun Dai, Robert Z Orlowski, Steven Grant
The role of the positive RNA Pol II regulator, P-TEFb (positive transcription elongation factor b), in maintenance of the anti-apoptotic protein Mcl-1 and bortezomib (btz) resistance was investigated in human multiple myeloma (MM) cells. Mcl-1 was up-regulated in all MM lines tested, including bortezomib-resistant lines, human MM xenograft mouse models, and primary CD138(+) MM cells. Mcl-1 over-expression significantly reduced bortezomib lethality, indicating a functional role for Mcl-1 in bortezomib resistance...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28923482/the-optimal-regulation-mode-of-bcl-2-apoptotic-switch-revealed-by-bistability-analysis
#8
Zhiyong Yin, Hong Qi, Lili Liu, Zhen Jin
In most cell types, apoptosis occurs by the mitochondrial outer membrane permeability (MOMP)-mediated pathway, which is controlled by Bcl-2 family proteins (often referred to as Bcl-2 apoptotic switch). These proteins, which display a range of bioactivities, can be divided into four types: effectors, inhibitors, activators and sensitizers. Although the complex interactions among Bcl-2 family members have been studied intensively, a unifying hypothesis for the mechanism they use to regulate MOMP remains elusive...
September 18, 2017: Bio Systems
https://www.readbyqxmd.com/read/28901269/recent-advances-in-cancer-drug-development-targeting-induced-myeloid-cell-leukemia-1-mcl-1-differentiation-protein
#9
Mohammad Abid, Yogesh A Sonawane, Jacob I Contreras, Sandeep Rana, Amarnath Natarajan
BACKGROUND: Anti-apoptotic members of the Bcl-2 family of proteins are upregulated in a majority of cancers and are potential therapeutic targets. Fragment-based design led to the development of clinical candidates that target Bcl-xL/Bcl-2. Although these Bcl-xL/Bcl-2 inhibitors showed promise in pre-clinical studies, resistance was observed to several Bcl-xL inhibitors, when used alone. This has been attributed to the over-expression of Mcl-1, another member of the Bcl-2 family of proteins...
September 11, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28868037/bh3-mimetics-for-the-treatment-of-prostate-cancer
#10
Philipp Wolf
Despite improved diagnostic and therapeutic intervention, advanced prostate cancer (PC) remains incurable. The acquired resistance of PC cells to current treatment protocols has been traced to apoptosis resistance based on the upregulation of anti-apoptotic proteins of the Bcl-2 family. The use of BH3 mimetics, mimicking pro-apoptotic activator or sensitizer proteins of the intrinsic apoptotic pathway, is therefore a promising treatment strategy. The present review gives an overview of preclinical and clinical studies with pan- and specific BH3 mimetics as sensitizers for cell death and gives an outlook how they could be effectively used for the therapy of advanced PC in future...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28844952/targeting-cholangiocarcinoma
#11
REVIEW
Joachim C Mertens, Sumera Rizvi, Gregory J Gores
Cholangiocarcinoma (CCA) represents a diverse group of epithelial cancers associated with the biliary tract, and can best be stratified anatomically into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subsets. Molecular profiling has identified genetic aberrations associated with these anatomic subsets. For example, IDH catalytic site mutations and constitutively active FGFR2 fusion genes are predominantly identified in iCCA, whereas KRAS mutations and PRKACB fusions genes are identified in pCCA and dCCA...
August 24, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28843007/bcl-2-protects-tk6-cells-against-hydroquinone-induced-apoptosis-through-parp-1-cytoplasm-translocation-and-stabilizing-mitochondrial-membrane-potential
#12
Yuting Chen, Shaoyun Chen, Hairong Liang, Hui Yang, Linhua Liu, Kairu Zhou, Longmei Xu, Jiaxian Liu, Lin Yun, Bei Lai, Li Song, Hao Luo, Jianming Peng, Zhidong Liu, Yongmei Xiao, Wen Chen, Huanwen Tang
B cell leukemia/lymphoma-2 (Bcl-2) suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating mitochondrial membrane potential (MMP). This study aimed to investigate the role of Bcl-2 in controlling the mitochondrial pathway of apoptosis during hydroquinone (HQ)-induced TK6 cytotoxicity. In this study, HQ, one metabolite of benzene, decreased the MMP in a concentration-dependent manner and induced the generation of reactive oxygen species (ROS), the activation of the DNA damage marker γ-H2AX, and production of the DNA damage-responsive enzyme poly(ADP-ribose)polymerase-1 (PARP-1)...
August 26, 2017: Environmental and Molecular Mutagenesis
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/28804913/on-bh3-mimetics-and-ca-2-signaling
#14
Pawel E Ferdek, Monika A Jakubowska
Preclinical Research BH3 mimetics are anticancer agents that reproduce the spatial arrangement of the BH3 domain of Bcl-2 family proteins. Just like the BH3-only proteins, these compounds bind to the hydrophobic cleft of the pro-survival Bcl-2 members such as Bcl-2 or Bcl-xL, and disrupt their heterodimerization with pro-apoptotic Bax or Bak, sensitizing cells to chemotherapy. In recent years, it has become clear that Bcl-2 family proteins are engaged in regulation of intracellular Ca(2+) homeostasis, including Ca(2+) release from the intracellular stores as well as Ca(2+) fluxes across the plasma membrane...
September 2017: Drug Development Research
https://www.readbyqxmd.com/read/28802066/targeting-senescent-cholangiocytes-and-activated-fibroblasts-with-bcl-xl-inhibitors-ameliorates-fibrosis-in-mdr2-mice
#15
Anja Moncsek, Mohammed S Al-Suraih, Christy E Trussoni, Steven P O'Hara, Patrick L Splinter, Camille Zuber, Eleonora Patsenker, Piero V Valli, Christian D Fingas, Achim Weber, Yi Zhu, Tamar Tchkonia, James L Kirkland, Gregory J Gores, Beat Müllhaupt, Nicholas F LaRusso, Joachim C Mertens
Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASF), which are drivers of fibrosis. The activated phenotype of ASF is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASF and explored a combined targeting strategy to deplete senescent cholangiocytes and ASF from fibrotic tissue to ameliorate liver fibrosis...
August 12, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28799432/targeted-therapies-in-acute-myeloid-leukemia-a-focus-on-flt-3-inhibitors-and-abt199
#16
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/28768804/synergistic-action-of-the-mcl-1-inhibitor-s63845-with-current-therapies-in-preclinical-models-of-triple-negative-and-her2-amplified-breast-cancer
#17
Delphine Merino, James R Whittle, François Vaillant, Antonin Serrano, Jia-Nan Gong, Goknur Giner, Ana Leticia Maragno, Maïa Chanrion, Emilie Schneider, Bhupinder Pal, Xiang Li, Grant Dewson, Julius Gräsel, Kevin Liu, Najoua Lalaoui, David Segal, Marco J Herold, David C S Huang, Gordon K Smyth, Olivier Geneste, Guillaume Lessene, Jane E Visvader, Geoffrey J Lindeman
The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer...
August 2, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28767402/mimicking-the-bim-bh3-domain-overcomes-resistance-to-egfr-tyrosine-kinase-inhibitors-in-egfr-mutant-non-small-cell-lung-cancer
#18
Jinjing Xia, Hao Bai, Bo Yan, Rong Li, Minhua Shao, Liwen Xiong, Baohui Han
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied to treat EGFR-mutant non-small cell lung cancer (NSCLC). BIM is a BH3 domain-containing protein encoded by BCL2L11. Some EGFR-mutant NSCLC patients showing BIM deletion polymorphism are resistant to EGFR TKIs. We retrospectively investigated BIM deletion polymorphism in NSCLC patients, its correlation with EGFR TKI (erlotinib) resistance, and the mechanism underlying the drug resistance. Among 245 EGFR-mutant NSCLC patients examined, BIM deletion polymorphism was detected in 43 (12...
July 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28741496/targeting-bcl-2-like-proteins-to-kill-cancer-cells
#19
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/28741484/suzanne-cory-life-and-death-switches-the-rise-of-bh3-mimetics
#20
(no author information available yet)
No abstract text is available yet for this article.
October 2016: Trends in Cancer
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