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https://www.readbyqxmd.com/read/28740556/yd277-suppresses-triple-negative-breast-cancer-partially-through-activating-the-endoplasmic-reticulum-stress-pathway
#1
Zekun Chen, Qiuju Wu, Ye Ding, Wenhui Zhou, Rong Liu, Haiying Chen, Jia Zhou, Jing Feng, Ceshi Chen
Triple-negative breast cancer (TNBC) is an aggressive malignancy with poor clinical outcomes. YD277 is a novel small molecule derived from ML264, a KLF5 inhibitor that elicits cytotoxic effects in colon cancer cell lines. Our previous studies suggest that Krüpple-like factor 5 (KLF5) is a promising therapeutic target for TNBC. In this study, we demonstrated that YD277 significantly induced G1 cell cycle arrest and apoptosis in MDA-MB-231 and MDA-MB-468 TNBC cells, independent of KLF5 inhibition. YD277 also reduced the protein expression levels of Cyclin D1, Bcl2 and Bclxl and promoted the expression of p21 and p27...
2017: Theranostics
https://www.readbyqxmd.com/read/28733544/identification-of-lefty-as-a-molecular-marker-for-ovarian-clear-cell-carcinoma
#2
Masashi Akiya, Masaaki Yamazaki, Toshihide Matsumoto, Yusuke Kawashima, Yasuko Oguri, Sabine Kajita, Daiki Kijima, Risako Chiba, Ako Yokoi, Hiroyuki Takahashi, Yoshio Kodera, Makoto Saegusa
To identify proteins involved in ovarian clear cell carcinoma (OCCCa), shotgun proteomics analysis was applied using formalin-fixed and paraffin-embedded samples of ovarian carcinoma. Analysis of 1521 proteins revealed that 52 were differentially expressed between four OCCCa and 12 non-OCCCa samples. Of the highly expressed proteins in OCCCa, we focused on left-right determination factor (LEFTY), a novel member of the transforming growth factor-β superfamily. In 143 cases of ovarian epithelial carcinoma including 99 OCCCas and 44 non-OCCCas, LEFTY expression at both mRNA and protein levels was significantly higher in OCCCas compared with non-OCCCas, with the mRNA expression of LEFTY1 being predominant compared to that of LEFTY2...
June 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28723622/dual-targeting-of-mdm2-and-bcl2-as-a-therapeutic-strategy-in-neuroblastoma
#3
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/28720543/involvement-of-the-bh3-only-pro-apoptotic-bik-nbk-in-braf-mek-inhibitor-induced-apoptosis-in-melanoma-cell-lines
#4
Andreas Borst, Sebastian Haferkamp, Johannes Grimm, Manuel Rösch, Guannan Zhu, Sen Guo, Chunying Li, Tianwen Gao, Svenja Meierjohann, David Schrama, Roland Houben
In patients with BRAF-mutated melanoma specific inhibitors of BRAF(V600E) and MEK1/2 frequently induce initial tumor reduction, frequently followed by relapse. As demonstrated previously, BRAF(V600E)-inhibition induces apoptosis only in a fraction of treated cells, while the remaining arrest and survive providing a source or a niche for relapse. To identify factors contributing to the differential initial response towards BRAF/MEK inhibition, we established M14 melanoma cell line-derived single cell clones responding to treatment with BRAF inhibitor vemurafenib and MEK inhibitor trametinib predominantly with either cell cycle arrest (CCA-cells) or apoptosis (A-cells)...
July 15, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28716711/epigenetic-silencing-of-mirna-143-regulates-apoptosis-by-targeting-bcl2-in-human-intervertebral-disc-degeneration
#5
Kangcheng Zhao, Yukun Zhang, Kang Liang, Yu Song, Kun Wang, Shuai Li, Xinghuo Wu, Wenbin Hua, Zengwu Shao, Shuhua Yang, Cao Yang
Accumulating evidence indicates that microRNAs can regulate the apoptosis of various cells. Apoptosis of nucleus pulposus cells plays an important role in the progression of intervertebral disc degeneration. The aim of this study is to investigate whether microRNA-143 (miRNA-143) is involved in the progression of intervertebral disc degeneration. In this study, the expression of miRNA-143 and its biological modulatory effects were examined. Messenger RNA and protein expression of miRNA-143 and B-cell lymphoma-2 (BCL2) in both normal and degenerative disc tissues was determined by using RT-PCR and western-blot assays...
July 14, 2017: Gene
https://www.readbyqxmd.com/read/28710745/the-pan-bcl2-inhibitor-at101-activates-the-intrinsic-apoptotic-pathway-and-causes-dna-damage-in-acute-myeloid-leukemia-stem-like-cells
#6
Leisi Zhang, Yong Zhou, Kai Chen, Pengcheng Shi, Yin Li, Manman Deng, Zhiwu Jiang, Xiangmeng Wang, Peng Li, Bing Xu
BACKGROUND: Leukemia stem cells (LSCs) are considered to be the cause of treatment failure and relapse in acute myeloid leukemia (AML). Overexpression of the Bcl-2 family of anti-apoptotic proteins such as Bcl-2, Bcl-xl, and Mcl-1 accounts for survival and self-renewal of LSCs. AT101 binds to the BH3 motif of all Bcl-2 family anti-apoptotic proteins and demonstrates anti-tumor activity in multiple types of tumor. Thus, we hypothesized that this agent might have the potential to deplete LSCs...
July 14, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28694085/baseline-characteristics-predicting-very-good-outcome-of-allogeneic-hematopoietic-cell-transplantation-in-young-patients-with-high-cytogenetic-risk-chronic-lymphocytic-leukemia%C3%A2-a-retrospective-analysis-from-the-chronic-malignancies-working-party-of-the-ebmt
#7
Michel van Gelder, Dimitris Ziagkos, Liesbeth de Wreede, Anja van Biezen, Peter Dreger, Martin Gramatzki, Matthias Stelljes, Niels Smedegaard Andersen, Nicolaas Schaap, Antonin Vitek, Dietrich Beelen, Vesa Lindström, Jürgen Finke, Jacob Passweg, Matthias Eder, Maciej Machaczka, Julio Delgado, William Krüger, Luděk Raida, Gerard Socié, Pavel Jindra, Boris Afanasyev, Eva Wagner, Yves Chalandon, Anja Henseler, Stefan Schoenland, Nicolaus Kröger, Johannes Schetelig
BACKGROUND: Patients with genetically high-risk relapsed/refractory chronic lymphocytic leukemia have shorter median progression-free survival (PFS) with kinase- and BCL2-inhibitors (KI, BCL2i). Allogeneic hematopoietic stem cell transplantation (alloHCT) may result in sustained PFS, especially in younger patients because of its age-dependent non-relapse mortality (NRM) risk, but outcome data are lacking for this population. PATIENTS AND METHODS: Risk factors for 2-year NRM and 8-year PFS were identified in patients < 50 years in an updated European Society for Blood and Marrow Transplantation registry cohort (n = 197; median follow-up, 90...
June 17, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28693188/consecutive-stimulation-of-hbsag-promotes-the-viability-of-the-human-b-lymphoblastoid-cell-line-im-9-through-regulating-the-sirt1-nf-%C3%AE%C2%BAb-pathway
#8
Jian Bo, Xiaojuan Wang, Jie Li, Wenqing Wang, Jinqian Zhang
Patients with chronic HBV infection have been reported to suffer a significantly increased risk of NHL, but the underlying mechanisms remain to be clearly explained. The aim of the present study was to clarify the relationship between chronic HBV infection and NHL development. Fluorescence-activated cell sorting, Annexin V/7-aminoactinomycin D staining and MTS assay were used to analyze the rate of apoptosis and cell viability. In addition, western blotting was used to detect protein expression. The effects of the activator of SIRT1, SRT1720, and the inhibitor of SIRT1, nicotinamide, were also analyzed...
July 2017: Oncology Letters
https://www.readbyqxmd.com/read/28676034/cathepsin-b-inhibitor-improves-developmental-competency-and-cryo-tolerance-of-in-vitro-ovine-embryos
#9
M Pezhman, S M Hosseini, S Ostadhosseini, Sh Rouhollahi Varnosfaderani, F Sefid, M H Nasr-Esfahani
BACKGROUND: Cathepsin B is a lysosomal cysteine protease involved in apoptosis and oocytes which have lower developmental competence show higher expression of Cathepsin B. Furthermore, expression of Cathepsin B show a decreasing trend from oocyte toward blastocyst stage. RESULTS: Present study assessed the effect of cathepsin B inhibitor, E-64, on developmental competency and cryo-survival of pre-implantation ovine IVF derived embryos. Cathepsin B inhibitor was added during day 3 to 8 of development...
July 4, 2017: BMC Developmental Biology
https://www.readbyqxmd.com/read/28663582/bet-protein-proteolysis-targeting-chimera-protac-exerts-potent-lethal-activity-against-mantle-cell-lymphoma-cells
#10
B Sun, W Fiskus, Y Qian, K Rajapakshe, K Raina, K G Coleman, A P Crew, A Shen, D T Saenz, C P Mill, A J Nowak, N Jain, L Zhang, M Wang, J D Khoury, C Coarfa, C M Crews, K N Bhalla
Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and NFkB target genes, which undermines the growth and survival of MCL cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells...
June 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28659338/high-throughput-profiling-of-signaling-networks-identifies-mechanism-based-combination-therapy-to-eliminate-microenvironmental-resistance-in-acute-myeloid-leukemia
#11
Zhihong Zeng, Wenbin Liu, Twee Tsao, YiHua Qiu, Yang Zhao, Ismael Samudio, Dos D Sarbassov, Steven M Kornblau, Keith A Baggerly, Hagop M Kantarjian, Marina Konopleva, Michael Andreeff
The bone marrow microenvironment is known to provide a survival advantage to residual acute myeloid leukemia cells, possibly contributing to disease recurrence. The mechanisms by which stroma in the microenvironment regulates leukemia survival remain largely unknown. Using reverse phase-protein array technology, we profiled 53 key protein molecules in 11 signaling pathways in 20 primary acute myeloid leukemia samples and two cell lines, aiming to understand stroma-mediated signaling modulation in response to the targeted agents temsirolimus (MTOR), ABT737 (BCL2/BCL-XL), and Nutlin-3a (MDM2), and to identify the effective combination therapy targeting acute myeloid leukemia in the context of the leukemia microenvironment...
June 28, 2017: Haematologica
https://www.readbyqxmd.com/read/28655725/chemical-chaperone-4-phenyl-butyric-acid-4pba-reduces-hepatocellular-lipid-accumulation-and-lipotoxicity-through-induction-of-autophagy
#12
Ashraf U Nissar, Love Sharma, Malik A Mudasir, Lone A Nazir, Sheikh A Umar, Parduman R Sharma, Ram A Vishwakarma, Sheikh A Tasduq
Defective autophagy has been linked to lipotoxicity in several cellular models. We aimed to investigate autophagy in lipid stimulated hepatoma (Huh7) cells and tested whether 4-Phenyl butyric acid (4PBA), a chemical chaperone, has a beneficial role in hepatic fat accumulation and lipotoxicity. We report that long-term (24h) exposure of hepatocytes to palmitate block autophagic flux that leads to lipid accumulation and cell death. Western blotting analysis showed increased accumulation of SQSTM1/P62, decreased expression of Beclin1 and Atg7 in palmitate-treated cells...
June 27, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28653617/replication-study-inhibition-of-bet-recruitment-to-chromatin-as-an-effective-treatment-for-mll-fusion-leukaemia
#13
Xiaochuan Shan, Juan Jose Fung, Alan Kosaka, Gwenn Danet-Desnoyers
In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Fung et al., 2015), that described how we intended to replicate selected experiments from the paper "Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia" (Dawson et al., 2011). Here, we report the results of those experiments. We found treatment of MLL-fusion leukaemia cells (MV4;11 cell line) with the BET bromodomain inhibitor I-BET151 resulted in selective growth inhibition, whereas treatment of leukaemia cells harboring a different oncogenic driver (K-562 cell line) did not result in selective growth inhibition; this is similar to the findings reported in the original study (Figure 2A and Supplementary Figure 11A,B; Dawson et al...
June 27, 2017: ELife
https://www.readbyqxmd.com/read/28647470/bcl2-a-promising-cancer-therapeutic-target
#14
REVIEW
Gudapureddy Radha, Sathees C Raghavan
A remarkable characteristic of majority of cancer cells is that, they fail to undergo apoptosis, which in turn confers them a survival advantage over normal cells. Targeted cancer therapy aims at disrupting the functions of proteins that play an important role during cancer progression. Antiapoptotic protein, BCL2, is one such protein that is highly upregulated in many cancers as compared to normal cells, making it an ideal target for cancer therapy. Although, several BCL2 targeting agents have been investigated over the past 30 years, very few have exhibited any clinical significance...
June 21, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28643758/effects-of-ef-24-rad001-and-paclitaxel-on-the-expression-profiles-of-apoptotic-and-anti-apoptotic-genes
#15
Ebru Alp, Akin Yilmaz, Hacer Ilke Onen, Emine Sevda Menevse
CONTEXT: Cancer cells exert differential responses to chemotherapeutics and inhibitors. To the best of our knowledge, a few or no research has been performed until now to determine the effect of EF-24 and RAD001 on MDA-MB-231 breast cancer cells with regard to mRNA expression of apoptotic and anti-apoptotic genes. AIMS: In this study, we aimed to investigate the mRNA expression levels of apoptotic (caspase 2 [CASP2], CASP8, and CASP9) and anti-apoptotic (B-cell lymphoma 2 [BCL2] and BCL2-like protein 1 [BCL2L1]) genes after exposure to paclitaxel, EF-24, and RAD001 in MDA-MB-231 cells...
April 2017: Journal of Cancer Research and Therapeutics
https://www.readbyqxmd.com/read/28631441/genetic-landscape-and-deregulated-pathways-in-b-cell-lymphoid-malignancies
#16
R Rosenquist, S Beà, M-Q Du, B Nadel, Q Pan-Hammarström
With the introduction of next-generation sequencing, the genetic landscape of the complex group of B-cell lymphoid malignancies has rapidly been unravelled in recent years. This has provided important information about recurrent genetic events and identified key pathways deregulated in each lymphoma subtype. In parallel, there has been intense search and development of novel types of targeted therapy that 'hit' central mechanisms in lymphoma pathobiology, such as BTK, PI3K or BCL2 inhibitors. In this review, we will outline the current view of the genetic landscape of selected entities: follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma...
June 20, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28628119/differential-expression-of-mir16-in-glioblastoma-and-glioblastoma-stem-cells-their-correlation-with-proliferation-differentiation-metastasis-and-prognosis
#17
R Tian, J Wang, H Yan, J Wu, Q Xu, X Zhan, Z Gui, M Ding, J He
The function of miR16 in multiforme glioblastoma multiforme (GBM) and its stem cells (GSCs) remains elusive. To this end, we investigated the patterns of miR16 expression in these cells and their correlation with malignant behaviors and clinical outcomes. The levels of miR16 and its targeted genes in tumor tissue of GBM and GBM SGH44, U87, U251 cells as well as their stem cell counterparts were measured by qRT-PCR or western blot or immunohistochemistry. Luciferase reporter assay was used to confirm the binding of miR16 to 3'-UTR of its target genes...
June 19, 2017: Oncogene
https://www.readbyqxmd.com/read/28619982/jak1-2-and-bcl2-inhibitors-synergize-to-counteract-bone-marrow-stromal-cell-induced-protection-of-aml
#18
Riikka Karjalainen, Tea Pemovska, Mihaela Popa, Minxia Liu, Komal K Javarappa, Muntasir M Majumder, Bhagwan Yadav, David Tamborero, Jing Tang, Dmitrii Bychkov, Mika Kontro, Alun Parsons, Minna Suvela, Mireia Mayoral Safont, Kimmo Porkka, Tero Aittokallio, Olli Kallioniemi, Emmet McCormack, Bjørn T Gjertsen, Krister Wennerberg, Jonathan Knowles, Caroline A Heckman
The bone marrow (BM) provides a protective microenvironment to support the survival of leukemic cells and influence their response to therapeutic agents. In acute myeloid leukemia (AML), the high rate of relapse may in part be due to the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the impact of the BM microenvironment on drug responses in AML, we conducted a comprehensive evaluation of 304 inhibitors, including approved and investigational agents, comparing ex vivo responses of primary AML cells in BM stroma-derived and standard culture conditions...
June 15, 2017: Blood
https://www.readbyqxmd.com/read/28610850/dietary-myo-inositol-deficiency-decreased-the-growth-performances-and-impaired-intestinal-physical-barrier-function-partly-relating-to-nrf2-jnk-e2f4-and-mlck-signaling-in-young-grass-carp-ctenopharyngodon-idella
#19
Shuang-An Li, Wei-Dan Jiang, Lin Feng, Yang Liu, Pei Wu, Jun Jiang, Sheng-Yao Kuang, Ling Tang, Wu-Neng Tang, Yong-An Zhang, Xu Tang, He-Qun Shi, Xiao-Qiu Zhou
In this study, we investigated the effects of dietary myo-inositol on the growth and intestinal physical barrier functions of young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp (221.83 ± 0.84 g) were fed six diets containing graded levels of myo-inositol (27.0, 137.9, 286.8, 438.6, 587.7 and 737.3 mg/kg) for 10 weeks. After the growth trial, fish were challenged with Aeromonas hydrophila for 14 days. The results indicated that compared with optimal myo-inositol levels, myo-inositol deficiency (27...
August 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28606806/bcl2-induced-by-lamtor3-mapk-is-a-druggable-target-of-chemoradioresistance-in-mesenchymal-lung-cancer
#20
Ok-Seon Kwon, Soon-Ki Hong, Soo-Jung Kwon, Young-Hyun Go, Ensel Oh, Hyuk-Jin Cha
Mesenchymal-type cancers after epithelial mesenchymal transition (EMT) were recently shown to acquire chemoresistance through expressing EMT specific transcription factors. However, druggable (or actionable) target(s) for chemoresistance in mesenchymal-type lung cancers remain unidentified. Here, we used a public clinical genomic database and mesenchymal lung cancer cells (MLCC) model derived from the A549 lung adenocarcinoma cell line to demonstrate that BCL2 expression, which is highly induced in mesenchymal-type lung cancers, as a predictor of poor prognosis in mesenchymal lung cancer patients and association with acquired chemoradioresistance...
June 10, 2017: Cancer Letters
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