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https://www.readbyqxmd.com/read/29733883/distinct-apoptotic-blocks-mediate-resistance-to-panher-inhibitors-in-her2-breast-cancer-cells
#1
Bahriye Karakas, Yeliz Ozmay, Huveyda Basaga, Ozgur Gul, Ozgur Kutuk
Despite the development of novel targeted therapies, de novo or acquired chemoresistance remains a significant factor for treatment failure in breast cancer therapeutics. Neratinib and dacomitinib are irreversible panHER inhibitors, which block their autophosphorylation and downstream signaling. Moreover, neratinib and dacomitinib have been shown to activate cell death in HER2-overexpressing cell lines. Here we showed that increased MCL1 and decreased BIM and PUMA mediated resistance to neratinib in ZR-75-30 and SKBR3 cells while increased BCL-XL and BCL-2 and decreased BIM and PUMA promoted neratinib resistance in BT474 cells...
May 4, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29732004/s55746-is-a-novel-orally-active-bcl-2-selective-and-potent-inhibitor-that-impairs-hematological-tumor-growth
#2
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/29723246/early-changes-in-rps6-phosphorylation-and-bh3-profiling-predict-response-to-chemotherapy-in-aml-cells
#3
Martin Grundy, Thomas Jones, Liban Elmi, Michael Hall, Adam Graham, Nigel Russell, Monica Pallis
Blasts from different patients with acute myeloid leukemia (AML) vary in the agent(s) to which they are most responsive. With a myriad of novel agents to evaluate, there is a lack of predictive biomarkers to precisely assign targeted therapies to individual patients. Primary AML cells often survive poorly in vitro, thus confounding conventional cytotoxicity assays. The purpose of this work was to assess the potential of two same-day functional predictive assays in AML cell lines to predict long-term response to chemotherapy...
2018: PloS One
https://www.readbyqxmd.com/read/29716994/folding-and-binding-pathways-of-bh3-only-proteins-are-encoded-within-their-intrinsically-disordered-sequence-not-templated-by-partner-proteins
#4
Michael D Crabtree, Carolina A T F Mendonça, Quenton R Bubb, Jane Clarke
Intrinsically disordered regions are present in one third of eukaryotic proteins and are overrepresented in cellular processes such as signaling, suggesting that intrinsically disordered proteins (IDPs) may have a functional advantage over folded proteins. Upon interacting with a partner macromolecule, a subset of IDPs can fold and bind to form a well-defined three-dimensional conformation. For example, disordered BH3-only proteins bind promiscuously to a large number of homologous BCL-2-family proteins, where they fold to a helical structure in a groove on the BCL-2-like protein surface...
May 1, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29682179/antiapoptotic-bcl-2-proteins-determine-sorafenib-regorafenib-resistance-and-bh3-mimetic-efficacy-in-hepatocellular-carcinoma
#5
Anna Tutusaus, Milica Stefanovic, Loreto Boix, Blanca Cucarull, Aynara Zamora, Laura Blasco, Pablo García de Frutos, Maria Reig, Jose C Fernandez-Checa, Montserrat Marí, Anna Colell, Jordi Bruix, Albert Morales
Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29518473/gene-expression-network-regulated-by-dna-methylation-and-microrna-during-microcystin-leucine-arginine-induced-malignant-transformation-in-human-hepatocyte-l02-cells
#6
Hong-Qiang Chen, Ji Zhao, Yan Li, Li-Xiong He, Yu-Jing Huang, Wei-Qun Shu, Jia Cao, Wen-Bin Liu, Jin-Yi Liu
Microcystin (MC) is a cyclic heptapeptide compound which could lead to the development of hepatocellular carcinoma. However, the underlying epigenetic regulation mechanism is largely unknown. In this study, microcystin-LR (L: lysine, R: arginine, MC-LR) was used to induce the malignant transformation of human hepatocyte L02 cell line. The profile of gene expression, microRNA (miRNA) and DNA methylation were detected through high-throughput sequencing. Compared with control group, the expression of 826 genes and 187 miRNAs changed significantly in MC-LR treated group...
June 1, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29408011/bh3-mimetics-as-anti-fibrotic-therapy-unleashing-the-mitochondrial-pathway-of-apoptosis-in-myofibroblasts
#7
REVIEW
Tobias Kuehl, David Lagares
Organs and tissues in mammals can undergo self-repair following injury. However, chronic or severe tissue injury leads to the development of dense scar tissue or fibrosis at the expense of regeneration. The identification of novel therapeutic strategies aiming at reversing fibrosis is therefore a major clinical unmet need in regenerative medicine. Persistent activation of scar-forming myofibroblasts distinguishes non-resolving pathological fibrosis from self-limited physiological wound healing. Thus, therapeutic strategies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in fibrotic diseases...
January 31, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/29358277/intracellular-bh3-profiling-reveals-shifts-in-antiapoptotic-dependency-in-human-b-cell-maturation-and-mitogen-stimulated-proliferation
#8
Joanne Dai, Micah A Luftig
Apoptosis is critical to B cell maturation, but studies of apoptotic regulation in primary human B cells is lacking. In this study, we sought to better understand the mechanisms of apoptotic regulation in normal and activated B cells. Using intracellular BH3 profiling, we defined the Bcl2 dependency of B cell subsets from human peripheral blood and tonsillar lymphoid tissue as well as mitogen-activated B cells. We found that naive and memory B cells were BCL-2-dependent, whereas germinal center B cells were MCL-1-dependent and plasma cells were BCL-XL -dependent...
March 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29316737/the-effect-of-lipopolysaccharide-on-noxa-expression-is-mediated-through-irf1-3-and-7
#9
Sujan Piya, Tae-Hyoung Kim
Lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, elicits the secretion of cytokines, such as interferons, that stimulate the host defense system. Previously, we demonstrated that interferons induce interferon regulatory factors (IRFs) 1, 3, and 7, which regulate the transcription of Noxa and alter the expression profiles of Bcl-2 family proteins in tumors. However, the immediate consequences of LPS stimulation on Noxa and BH3 expression in tumor cells remain uncharacterized...
March 28, 2018: Journal of Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29298347/predicting-effective-pro-apoptotic-anti-leukaemic-drug-combinations-using-co-operative-dynamic-bh3-profiling
#10
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/29237758/targeted-apoptosis-of-myofibroblasts-with-the-bh3-mimetic-abt-263-reverses-established-fibrosis
#11
David Lagares, Alba Santos, Paula E Grasberger, Fei Liu, Clemens K Probst, Rod A Rahimi, Norihiko Sakai, Tobias Kuehl, Jeremy Ryan, Patrick Bhola, Joan Montero, Mohit Kapoor, Murray Baron, Xaralabos Varelas, Daniel J Tschumperlin, Anthony Letai, Andrew M Tager
Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in diseases such as scleroderma, a heterogeneous autoimmune disease characterized by multiorgan fibrosis. We demonstrate that fibroblast-to-myofibroblast differentiation driven by matrix stiffness increases the mitochondrial priming (proximity to the apoptotic threshold) of these activated cells...
December 13, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29229991/bok-promotes-chemical-induced-hepatocarcinogenesis-in-mice
#12
Tatiana Rabachini, Yuniel Fernandez-Marrero, Matteo Montani, Giulio Loforese, Valentina Sladky, Zhaoyue He, Daniel Bachmann, Simone Wicki, Andreas Villunger, Deborah Stroka, Thomas Kaufmann
BCL-2-related ovarian killer (BOK) is a conserved and widely expressed BCL-2 family member with sequence homology to pro-apoptotic BAX and BAK, but with poorly understood pathophysiological function. Since several members of the BCL-2 family are critically involved in the regulation of hepatocellular apoptosis and carcinogenesis we aimed to establish whether loss of BOK affects diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. Short-term exposure to DEN lead to upregulation of BOK mRNA and protein in the liver...
December 11, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29077093/why-do-bcl-2-inhibitors-work-and-where-should-we-use-them-in-the-clinic
#13
REVIEW
Joan Montero, Antony Letai
Intrinsic apoptosis is controlled by the BCL-2 family of proteins but the complexity of intra-family interactions makes it challenging to predict cell fate via standard molecular biology techniques. We discuss BCL-2 family regulation and how to determine cells' readiness for apoptosis and anti-apoptotic dependence. Cancer cells often adopt anti-apoptotic defense mechanisms in response to oncogenic stress or anti-cancer therapy. However, by determining their anti-apoptotic addiction, we can use novel BH3 mimetics to overwhelm this apoptotic blockade...
January 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28960205/coordinated-repression-of-bim-and-puma-by-epstein-barr-virus-latent-genes-maintains-the-survival-of-burkitt-lymphoma-cells
#14
Leah Fitzsimmons, Andrew J Boyce, Wenbin Wei, Catherine Chang, Deborah Croom-Carter, Rosemary J Tierney, Marco J Herold, Andrew I Bell, Andreas Strasser, Gemma L Kelly, Martin Rowe
While the association of Epstein-Barr virus (EBV) with Burkitt lymphoma (BL) has long been recognised, the precise role of the virus in BL pathogenesis is not fully resolved. EBV can be lost spontaneously from some BL cell lines, and these EBV-loss lymphoma cells reportedly have a survival disadvantage. Here we have generated an extensive panel of EBV-loss clones from multiple BL backgrounds and examined their phenotype comparing them to their isogenic EBV-positive counterparts. We report that, while loss of EBV from BL cells is rare, it is consistently associated with an enhanced predisposition to undergo apoptosis and reduced tumorigenicity in vivo...
February 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28844952/targeting-cholangiocarcinoma
#15
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...
April 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28804127/discovery-of-novel-drug-sensitivities-in-t-pll-by-high-throughput-ex-vivo-drug-testing-and-mutation-profiling
#16
E I Andersson, S Pützer, B Yadav, O Dufva, S Khan, L He, L Sellner, A Schrader, G Crispatzu, M Oleś, H Zhang, S Adnan-Awad, S Lagström, D Bellanger, J P Mpindi, S Eldfors, T Pemovska, P Pietarinen, A Lauhio, K Tomska, C Cuesta-Mateos, E Faber, S Koschmieder, T H Brümmendorf, S Kytölä, E-R Savolainen, T Siitonen, P Ellonen, O Kallioniemi, K Wennerberg, W Ding, M-H Stern, W Huber, S Anders, J Tang, T Aittokallio, T Zenz, M Herling, S Mustjoki
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles...
March 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28802908/apoptosis-signaling-and-bcl-2-pathways-provide-opportunities-for-novel-targeted-therapeutic-strategies-in-hematologic-malignances
#17
REVIEW
Huanling Wu, L Jeffrey Medeiros, Ken H Young
Apoptosis is an essential biological process involved in tissue homeostasis and immunity. Aberrations of the two main apoptotic pathways, extrinsic and intrinsic, have been identified in hematological malignancies; many of these aberrations are associated with pathogenesis, prognosis and resistance to standard chemotherapeutic agents. Targeting components of the apoptotic pathways, especially the chief regulatory BCL-2 family in the intrinsic pathway, has proved to be a promising therapeutic approach for patients with hematological malignances, with the expectation of enhanced efficacy and reduced adverse events...
January 2018: Blood Reviews
https://www.readbyqxmd.com/read/28799432/targeted-therapies-in-acute-myeloid-leukemia-a-focus-on-flt-3-inhibitors-and-abt199
#18
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/28737741/rapidly-inducible-cas9-and-dsb-ddpcr-to-probe-editing-kinetics
#19
John C Rose, Jason J Stephany, William J Valente, Bridget M Trevillian, Ha V Dang, Jason H Bielas, Dustin J Maly, Douglas M Fowler
We developed a chemically inducible Cas9 (ciCas9) and a droplet digital PCR assay for double-strand breaks (DSB-ddPCR) to investigate the kinetics of Cas9-mediated generation and repair of DSBs in cells. ciCas9 is a rapidly activated, single-component Cas9 variant engineered by replacing the protein's REC2 domain with the BCL-xL protein and fusing an interacting BH3 peptide to the C terminus. ciCas9 can be tunably activated by a compound that disrupts the BCL-xL-BH3 interaction within minutes. DSB-ddPCR demonstrates time-resolved, highly quantitative, and targeted measurement of DSBs...
September 2017: Nature Methods
https://www.readbyqxmd.com/read/28724540/targeting-bcl-2-in-b-cell-lymphomas
#20
REVIEW
Matthew S Davids
The B-cell leukemia/lymphoma-2 (BCL-2) family of proteins governs the intrinsic pathway of mitochondrial apoptosis. Dysregulation of BCL-2 has long been known to be a crucial part of the pathophysiology of B-cell lymphomas; however, several early attempts to target this pathway therapeutically were unsuccessful because of toxicity, lack of efficacy, or both. Recently, a highly potent and selective oral BCL-2 antagonist, venetoclax, was approved in chronic lymphocytic leukemia, where it has proven to be highly active, even in patients with high-risk del(17p) disease...
August 31, 2017: Blood
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