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Leukemia chemoresistance

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https://www.readbyqxmd.com/read/28211885/the-novel-bmi-1-inhibitor-ptc596-downregulates-mcl-1-and-induces-p53-independent-mitochondrial-apoptosis-in-acute-myeloid-leukemia-progenitor-cells
#1
Y Nishida, A Maeda, M J Kim, L Cao, Y Kubota, J Ishizawa, A AlRawi, Y Kato, A Iwama, M Fujisawa, K Matsue, M Weetall, M Dumble, M Andreeff, T W Davis, A Branstrom, S Kimura, K Kojima
Disease recurrence is the major problem in the treatment of acute myeloid leukemia (AML). Relapse is driven by leukemia stem cells, a chemoresistant subpopulation capable of re-establishing disease. Patients with p53 mutant AML are at an extremely high risk of relapse. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is required for the self-renewal and maintenance of AML stem cells. Here we studied the effects of a novel small molecule inhibitor of BMI-1, PTC596, in AML cells. Treatment with PTC596 reduced MCL-1 expression and triggered several molecular events consistent with induction of mitochondrial apoptosis: loss of mitochondrial membrane potential, BAX conformational change, caspase-3 cleavage and phosphatidylserine externalization...
February 17, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28196625/-did-he-who-made-the-lamb-make-thee-new-developments-in-treating-the-fearful-symmetry-of-acute-myeloid-leukemia
#2
REVIEW
Gabriela Brumatti, Najoua Lalaoui, Andrew H Wei, John Silke
Malignant cells must circumvent endogenous cell death pathways to survive and develop into cancers. Acquired cell death resistance also sets up malignant cells to survive anticancer therapies. Acute Myeloid Leukemia (AML) is an aggressive blood cancer characterized by high relapse rate and resistance to cytotoxic therapies. Recent collaborative profiling projects have led to a greater understanding of the 'fearful symmetry' of the genomic landscape of AML, and point to the development of novel potential therapies that can overcome factors linked to chemoresistance...
February 11, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28177892/pevonedistat-a-nedd8-activating-enzyme-inhibitor-sensitizes-neoplastic-b-cells-to-death-receptor-mediated-apoptosis
#3
Cody Paiva, J Claire Godbersen, Taylor Rowland, Olga V Danilova, Christopher Danes, Allison Berger, Alexey V Danilov
While death receptor ligands (Fas and TRAIL) kill chemoresistant tumor cell lines, related therapies have limited clinical efficacy as single agents. Death receptor signaling is modulated by nuclear factor-κB (NFκB), a family of transcription factors which are constitutively active in B-cell malignancies. We and others have shown that pevonedistat, an investigational inhibitor of the NEDD8-activating enzyme, abrogates NFκB activity in B-cell neoplasia. Here we demonstrate that diffuse large B-cell lymphoma, particularly activated B-cell type, and primary chronic lymphocytic leukemia cells are re-sensitized to extrinsic apoptosis by pevonedistat...
February 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28160570/resistance-of-leukemia-cells-to-cytarabine-chemotherapy-is-mediated-by-bone-marrow-stroma-involves-cell-surface-equilibrative-nucleoside-transporter-1-removal-and-correlates-with-patient-outcome
#4
Patricia Macanas-Pirard, Richard Broekhuizen, Alfonso González, Claudia Oyanadel, Daniel Ernst, Patricia García, Viviana P Montecinos, Felipe Court, Mauricio Ocqueteau, Pablo Ramirez, Bruno Nervi
The interaction between acute myeloid leukemia cells (AML) with the bone marrow stroma cells (BMSCs) determines a protective environment that favors tumor development and resistance to conventional chemotherapy. We showed that BMSCs secrete soluble factors that protect AML cells from Ara-C induced cytotoxicity. This leukemia chemoresistance is associated with a decrease in the equilibrative nucleoside transporter (ENT1) activity by inducing removal of ENT1 from the cell surface. Reduction of cell proliferation was also observed with activation of AKT and mTOR-dependent cell survival pathways, which may also contribute to the tumor chemoprotection...
February 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28159741/biology-and-relevance-of-human-acute-myeloid-leukemia-stem-cells
#5
Daniel Thomas, Ravindra Majeti
Evidence of human acute myeloid leukemia stem cells (AML LSCs) was first reported nearly two decades ago through the identification of rare subpopulations of engrafting cells in xenotransplantation assays. These AML LSCs were shown to reside at the apex of a cellular hierarchy that initiates and maintains the disease, exhibiting properties of self-renewal, cell cycle quiescence, and chemoresistance. This cancer stem cell model offers an explanation for chemotherapy resistance and disease relapse, and implies that approaches to treatment must eradicate LSCs for cure...
February 3, 2017: Blood
https://www.readbyqxmd.com/read/28150717/wogonin-reversed-resistant-human-myelogenous-leukemia-cells-via-inhibiting-nrf2-signaling-by-stat3-nf-%C3%AE%C2%BAb-inactivation
#6
Xuefen Xu, Xiaobo Zhang, Yi Zhang, Lin Yang, Yicheng Liu, Shaoliang Huang, Lu Lu, Lingyi Kong, Zhiyu Li, Qinglong Guo, Li Zhao
Constitutive NF-E2-related factor 2 (Nrf2, NFE2L2) activation has been recently reported to play a pivotal role in enhancing cell survival and resistance to anticancer drugs in many tumors. Wogonin had strong reversal potency via reduction of Nrf2 mRNA in Adriamycin (ADR)-induced resistant human chronic myelogenous leukemia (CML) K562/A02, but the mechanism of reduction of Nrf2 mRNA was still unclear. In this study, we aimed to delineate the mechanism by which Wogonin suppressed transcription of Nrf2 in resistant CML cells and further evaluate the reversal effects of Wogonin on the established animal models...
February 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28125433/pi3k-%C3%AE-inhibition-using-cal-101-exerts-apoptotic-effects-and-increases-doxorubicin-induced-cell-death-in-pre-b-acute-lymphoblastic-leukemia-cells
#7
Ava Safaroghli-Azar, Davood Bashash, Parisa Sadreazami, Majid Momeny, Seyed H Ghaffari
The frequency of dysregulated PI3K in acute lymphoblastic leukemia (ALL) coupled with the critical role of this signaling pathway in the acquisition of chemoresistant phenotype lend compelling weight to the application of PI3K inhibitors for the treatment of ALL. In this study, we found that abrogation of the PI3K pathway using CAL-101, a selective inhibitor of PI3K p110-δ, exerts a cytotoxic effect against Nalm-6 pre-B-ALL cells. Our results showed that the growth-suppressive effect is mediated, at least partially, by G1 arrest as a result of upregulated p21...
January 25, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28069801/aurora-a-and-nf-%C3%AE%C2%BAb-survival-pathway-drive-chemoresistance-in-acute-myeloid-leukemia-via-the-traf-interacting-protein-tifa
#8
Tong-You Wade Wei, Pei-Yu Wu, Ting-Jung Wu, Hsin-An Hou, Wen-Chien Chou, Chieh-Lin Jerry Teng, Chih-Ru Lin, Jo-Mei Maureen Chen, Ting-Yang Lin, Hsiang-Chun Su, Chia-Chi Flora Huang, Chang-Tze Ricky Yu, Shih-Lan Hsu, Hwei-Fang Tien, Ming-Daw Tsai
Aurora A-dependent NF-κB signaling portends poor prognosis in acute myeloid leukemia (AML) and other cancers, but the functional basis underlying this association is unclear. Here, we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML. TIFA protein was overexpressed concurrently with Aurora A and NF-κB signaling factors in patients with de novo AML relative to healthy individuals and also correlated with poor prognosis...
January 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28054944/the-role-of-histone-protein-modifications-and-mutations-in-histone-modifiers-in-pediatric-b-cell-progenitor-acute-lymphoblastic-leukemia
#9
REVIEW
Szymon Janczar, Karolina Janczar, Agata Pastorczak, Hani Harb, Adam J W Paige, Beata Zalewska-Szewczyk, Marian Danilewicz, Wojciech Mlynarski
While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable...
January 3, 2017: Cancers
https://www.readbyqxmd.com/read/28044259/bortezomib-interferes-with-adhesion-of-b-cell-precursor-acute-lymphoblastic-leukemia-cells-through-sparc-up-regulation-in-human-bone-marrow-mesenchymal-stromal-stem-cells
#10
Masaki Iwasa, Yasuo Miura, Aya Fujishiro, Sumie Fujii, Noriko Sugino, Satoshi Yoshioka, Asumi Yokota, Terutoshi Hishita, Hideyo Hirai, Akira Andoh, Tatsuo Ichinohe, Taira Maekawa
The poor prognosis of adults with B cell precursor acute lymphoblastic leukemia (BCP-ALL) is attributed to leukemia cells that are protected by the bone marrow (BM) microenvironment. In the present study, we explored the pharmacological targeting of mesenchymal stromal/stem cells in BM (BM-MSCs) to eliminate chemoresistant BCP-ALL cells. Human BCP-ALL cells (NALM-6 cells) that adhered to human BM-MSCs (NALM-6/Ad) were highly resistant to multiple anti-cancer drugs, and exhibited pro-survival characteristics, such as an enhanced Akt/Bcl-2 pathway and increased populations in the G0 and G2/S/M cell cycle stages...
January 2, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28042875/the-pik3-mtor-dual-inhibitor-bez235-suppresses-proliferation-and-migration-and-reverses-multidrug-resistance-in-acute-myeloid-leukemia
#11
Lan Deng, Ling Jiang, Xiang-Hua Lin, Kuo-Fu Tseng, Yuan Liu, Xing Zhang, Rui-Hong Dong, Zhi-Gang Lu, Xiu-Ju Wang
Aberrant activation of the PI3K/Akt/mTOR pathway contributes to the proliferation of malignant cells, and may confer resistance to chemotherapy in various malignancies, including acute myeloid leukemia (AML). Chemoresistance is the major reason for relapse in AML. RAD001 (everolimus) has been used at d1 and d7 of an induction chemotherapy regimen for AML, which has acceptable toxicity and may improve conventional chemotherapeutic treatment. Dual inhibitors of PI3K and mTOR overcome some of the intrinsic disadvantages of rapamycin and its derivatives...
January 2, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28040726/role-of-znf224-in-cell-growth-and-chemoresistance-of-chronic-lymphocitic-leukemia
#12
Teresa Busiello, Michela Ciano, Simona Romano, Gaetano Sodaro, Olgavalentina Garofalo, Dario Bruzzese, Luigia Simeone, Federico Chiurazzi, Maria Fiammetta Romano, Paola Costanzo, Elena Cesaro
Chronic lymphocytic leukaemia (CLL) is associated with apoptosis resistance and defective control of cell growth. Our study describes for the first time a critical role in CLL for the KRAB-zinc finger protein ZNF224. High ZNF224 transcript levels were detected in CLL patients with respect to control cells. Moreover, ZNF224 expression was significantly lowered after conventional chemotherapy treatment in a subset of CLL patients. By in vitro experiments we confirmed that ZNF224 expression is suppressed by fludarabine and demonstrated that ZNF224 is involved in apoptosis resistance in CLL cells...
December 30, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27980223/extracellular-atp-induces-apoptosis-through-p2x7r-activation-in-acute-myeloid-leukemia-cells-but-not-in-normal-hematopoietic-stem-cells
#13
Valentina Salvestrini, Stefania Orecchioni, Giovanna Talarico, Francesca Reggiani, Cristina Mazzetti, Francesco Bertolini, Elisa Orioli, Elena Adinolfi, Francesco Di Virgilio, Annalisa Pezzi, Michele Cavo, Roberto M Lemoli, Antonio Curti
Recent studies have shown that high ATP levels exhibit direct cytotoxic effects on several cancer cells types. Among the receptors engaged by ATP, P2X7R is the most consistently expressed by tumors. P2X7R is an ATP-gated ion channel that could drive the opening of a non-selective pore, triggering cell-death signal. We previously demonstrated that acute myeloid leukemia (AML) cells express high level of P2X7R. Here, we show that P2X7R activation with high dose ATP induces AML blast cells apoptosis. Moreover, P2X7R is also expressed on leukemic stem/progenitor cells (LSCs) which are sensitive to ATP-mediated cytotoxicity...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/27974700/tunneling-nanotube-tnt-formation-is-downregulated-by-cytarabine-and-nf-%C3%AE%C2%BAb-inhibition-in-acute-myeloid-leukemia-aml
#14
Maria Omsland, Øystein Bruserud, Bjørn T Gjertsen, Vibeke Andresen
Acute myeloid leukemia (AML) is a bone marrow derived blood cancer where intercellular communication in the leukemic bone marrow participates in disease development, progression and chemoresistance. Tunneling nanotubes (TNTs) are intercellular communication structures involved in transport of cellular contents and pathogens, also demonstrated to play a role in both cell death modulation and chemoresistance. Here we investigated the presence of TNTs by live fluorescent microscopy and identified TNT formation between primary AML cells and in AML cell lines...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/27974648/alternative-rna-processing-of-topoisomerase-ii%C3%AE-in-etoposide-resistant-human-leukemia-k562-cells-intron-retention-results-in-a-novel-c-terminal-truncated-90-kda-isoform
#15
Ragu Kanagasabai, Lucas Serdar, Soumendrakrishna Karmahapatra, Corey A Kientz, Justin Ellis, Mary K Ritke, Terry S Elton, Jack C Yalowich
DNA topoisomerase IIα (TOP2α) is a prominent target for anticancer drugs whose clinical efficacy is often limited by chemoresistance. Using antibody specific for the N-terminal of TOP2α, immunoassays indicated the existence of two TOP2α isoforms, 170 and 90 kDa, present in K562 leukemia cells and in an acquired etoposide (VP-16)-resistant clone (K/VP.5). TOP2α/90 expression was dramatically increased in etoposide-resistant K/VP.5 compared with parental K562 cells. We hypothesized that TOP2α/90 was the translation product of novel alternatively processed pre-mRNA, confirmed by 3'-rapid amplification of cDNA ends, polymerase chain reaction, and sequencing...
January 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27973410/therapeutic-resistance-in-acute-myeloid-leukemia-the-role-of-non-coding-rnas
#16
REVIEW
Armin Zebisch, Stefan Hatzl, Martin Pichler, Albert Wölfler, Heinz Sill
Acute myeloid leukemia (AML) is caused by malignant transformation of hematopoietic stem or progenitor cells and displays the most frequent acute leukemia in adults. Although some patients can be cured with high dose chemotherapy and allogeneic hematopoietic stem cell transplantation, the majority still succumbs to chemoresistant disease. Micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNA fragments and act as key players in the regulation of both physiologic and pathologic gene expression profiles...
December 10, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27941792/loss-of-the-histone-methyltransferase-ezh2-induces-resistance-to-multiple-drugs-in-acute-myeloid-leukemia
#17
Stefanie Göllner, Thomas Oellerich, Shuchi Agrawal-Singh, Tino Schenk, Hans-Ulrich Klein, Christian Rohde, Caroline Pabst, Tim Sauer, Mads Lerdrup, Sigal Tavor, Friedrich Stölzel, Sylvia Herold, Gerhard Ehninger, Gabriele Köhler, Kuan-Ting Pan, Henning Urlaub, Hubert Serve, Martin Dugas, Karsten Spiekermann, Binje Vick, Irmela Jeremias, Wolfgang E Berdel, Klaus Hansen, Arthur Zelent, Claudia Wickenhauser, Lutz P Müller, Christian Thiede, Carsten Müller-Tidow
In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction of histone H3K27 trimethylation as a novel pathway of acquired resistance to tyrosine kinase inhibitors (TKIs) and cytotoxic drugs in AML. Low EZH2 protein levels correlated with poor prognosis in AML patients. Suppression of EZH2 protein expression induced chemoresistance of AML cell lines and primary cells in vitro and in vivo...
January 2017: Nature Medicine
https://www.readbyqxmd.com/read/27903981/nurse-like-cells-promote-cll-survival-through-lfa-3-cd2-interactions
#18
Frédéric Boissard, Marie Tosolini, Laetitia Ligat, Anne Quillet-Mary, Frederic Lopez, Jean-Jacques Fournié, Loic Ysebaert, Mary Poupot
In the tumoral micro-environment (TME) of chronic lymphocytic leukemia (CLL), nurse-like cells (NLC) are tumor-associated macrophages which play a critical role in the survival and chemoresistance of tumoral cells. This pro-survival activity is known to involve soluble factors, but few data are available on the relative role of cells cross-talk. Here, we used a transcriptome-based approach to systematically investigate the expression of various receptor/ligand pairs at the surface of NLC/CLL cells. Their relative contribution to CLL survival was assessed both by fluorescent microscopy to identify cellular interactions and by the use of functional tests to measure the impact of uncoupling these pairs with blocking monoclonal antibodies...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27903673/combining-anti-mir-155-with-chemotherapy-for-the-treatment-of-lung-cancers
#19
Katrien Van Roosbroeck, Francesca Fanini, Tetsuro Setoyama, Cristina Ivan, Cristian Rodriguez-Aguayo, Enrique Fuentes-Mattei, Lianchun Xiao, Ivan Vannini, Roxana Redis, Lucilla D'Abundo, Xinna Zhang, Milena S Nicoloso, Simona Rossi, Vianey Gonzalez-Villasana, Rajesha Rupaimoole, Manuela Ferracin, Fortunato Morabito, Antonino Neri, Peter Ruvolo, Vivian R Ruvolo, Chad V Pecot, Dino Amadori, Lynne Aruzzo, Steliana Calin, Xuemei Wang, M James You, Alessandra Ferrajoli, Robert Z Orlowski, William Plunkett, Tara Lichtenberg, Ramana V Davuluri, Ioana Berindan-Neagoe, Massimo Negrini, Ignacio I Wistuba, Kantarjian Hagop, Anil K Sood, Gabriel Lopez-Berestein, Michael J Keating, Muller Fabbri, George A Calin
Purpose The oncogenic miR-155 is upregulated in many human cancers and its expression is increased in more aggressive and therapy resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors. Experimental Design We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance...
November 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27902471/autophagy-autophagy-associated-adaptive-immune-responses-and-its-role-in-hematologic-malignancies
#20
REVIEW
Liangshun You, Shenhe Jin, Li Zhu, Wenbin Qian
Autophagy is a tightly regulated catabolic process that leads to the degradation of cytoplasmatic components such as aggregated/misfolded proteins and organelles through the lysosomal machinery. Recent studies suggest that autophagy plays such a role in the context of the anti-tumor immune response, make it an attractive target for cancer immunotherapy. Defective autophagy in hematopoietic stem cells may contribute to the development of hematologic malignancies, including leukemia, myelodysplastic syndrome, and lymphoproliferative disorder...
November 25, 2016: Oncotarget
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