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Bcl-2 protein inhibitors

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https://www.readbyqxmd.com/read/29348880/the-potential-mechanism-of-extracellular-high-mobility-group-box-1-protein-mediated-p53-expression-in-immune-dysfunction-of-t-lymphocytes
#1
Ying-Yi Luan, Min Jia, Hui Zhang, Fu-Jun Zhu, Ning Dong, Yong-Wen Feng, Ming Wu, Ya-Lin Tong, Yong-Ming Yao
In the present study, we examined the activity of p53 protein in Jurkat cells treated with high mobility group box-1 protein (HMGB1), thereafter we investigated the mechanism of extracellular HMGB1 mediated p53 expression in immune dysfunction of T lymphocytes. mRNA expression of p53, mdm2, and p21 was determined by Real-time reverse transcription-polymerase chain reaction(RT-PCR). The apoptotic rate of Jurkat cells was analyzed by flow cytometry. Expressions of bcl-2, bax, caspase-3, phosphorylated (p) extracellular signal-regulated kinase (ERK)1/2, ERK1/2, p-p38 mitogen-activated protein kinase (MAPK), p38 MAPK, and p-c-jun amino-terminal kinase (JNK)1/2 and JNK1/2 were simultaneously determined by Western blotting...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348439/dual-suppression-of-inner-and-outer-mitochondrial-membrane-functions-augments-apoptotic-responses-to-oncogenic-mapk-inhibition
#2
Madhavika N Serasinghe, Jesse D Gelles, Kent Li, Lauren Zhao, Franco Abbate, Marie Syku, Jarvier N Mohammed, Brateil Badal, Cuahutlehuanitzin A Rangel, Kyle L Hoehn, Julide Tok Celebi, Jerry Edward Chipuk
Mitogen-activated protein kinase (MAPK) pathway inhibitors show promise in treating melanoma, but are unsuccessful in achieving long-term remission. Concordant with clinical data, BRAFV600E melanoma cells eliminate glycolysis upon inhibition of BRAFV600E or MEK with the targeted therapies Vemurafenib or Trametinib, respectively. Consequently, exposure to these therapies reprograms cellular metabolism to increase mitochondrial respiration and restrain cell death commitment. As the inner mitochondrial membrane (IMM) is sub-organellar site of oxidative phosphorylation (OXPHOS), and the outer mitochondrial membrane (OMM) is the major site of anti-apoptotic BCL-2 protein function, we hypothesized that suppressing these critical mitochondrial membrane functions would be a rational approach to maximize the pro-apoptotic effect of MAPK inhibition...
January 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29344198/combination-of-cecropinxj-and-ly294002-induces-synergistic-cytotoxicity-and-apoptosis-in-human-gastric-cancer-cells-via-inhibition-of-the-pi3k-akt-signaling-pathway
#3
Li-Jie Xia, Yan-Ling Wu, Fu-Chun Zhang
The aim of the present study was to investigate the cytotoxic and apoptotic effects of cecropinXJ against human gastric cancer BGC823 cells, either alone, or in combination with a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. Cell viability and the apoptosis rate were measured using flow cytometry with Annexin-V staining. Additionally, the expression levels of several RAC-α serine/threonine kinase (Akt) phosphorylation-associated proteins and apoptosis-regulating proteins were evaluated by western blot analysis...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29343814/intrinsic-apoptotic-pathway-activation-increases-response-to-anti-estrogens-in-luminal-breast-cancers
#4
Michelle M Williams, Linus Lee, Thomas Werfel, Meghan M Morrison Joly, Donna J Hicks, Bushra Rahman, David Elion, Courtney McKernan, Violeta Sanchez, Monica V Estrada, Suleiman Massarweh, Richard Elledge, Craig Duvall, Rebecca S Cook
Estrogen receptor-α positive (ERα+) breast cancer accounts for approximately 70-80% of the nearly 25,0000 new cases of breast cancer diagnosed in the US each year. Endocrine-targeted therapies (those that block ERα activity) serve as the first line of treatment in most cases. Despite the proven benefit of endocrine therapies, however, ERα+ breast tumors can develop resistance to endocrine therapy, causing disease progression or relapse, particularly in the metastatic setting. Anti-apoptotic Bcl-2 family proteins enhance breast tumor cell survival, often promoting resistance to targeted therapies, including endocrine therapies...
January 17, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29340082/reciprocal-sensitivity-of-diffuse-large-b-cell-lymphoma-cells-to-bcl-2-inhibitors-bird-2-versus-venetoclax
#5
Tamara Vervloessem, Haidar Akl, Thomas Tousseyn, Humbert De Smedt, Jan B Parys, Geert Bultynck
Bcl-2 is often upregulated in cancers to neutralize the BH3-only protein Bim at the mitochondria. BH3 mimetics (e.g. ABT-199 (venetoclax)) kill cancer cells by targeting Bcl-2's hydrophobic cleft and disrupting Bcl-2/Bim complexes. Some cancers with elevated Bcl-2 display poor responses towards BH3 mimetics, suggesting an additional function for anti-apoptotic Bcl-2 in these cancers. Indeed, Bcl-2 via its BH4 domain prevents cytotoxic Ca2+ release from the endoplasmic reticulum (ER) by directly inhibiting the inositol 1,4,5-trisphosphate receptor (IP3R)...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339518/iterative-optimization-yields-mcl-1-targeting-stapled-peptides-with-selective-cytotoxicity-to-mcl-1-dependent-cancer-cells
#6
Raheleh Rezaei Araghi, Gregory H Bird, Jeremy A Ryan, Justin M Jenson, Marina Godes, Jonathan R Pritz, Robert A Grant, Anthony Letai, Loren D Walensky, Amy E Keating
Bcl-2 family proteins regulate apoptosis, and aberrant interactions of overexpressed antiapoptotic family members such as Mcl-1 promote cell transformation, cancer survival, and resistance to chemotherapy. Discovering potent and selective Mcl-1 inhibitors that can relieve apoptotic blockades is thus a high priority for cancer research. An attractive strategy for disabling Mcl-1 involves using designer peptides to competitively engage its binding groove, mimicking the structural mechanism of action of native sensitizer BH3-only proteins...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29339045/deficiency-of-dietary-pyridoxine-disturbed-the-intestinal-physical-barrier-function-of-young-grass-carp-ctenopharyngodon-idella
#7
Pei Wu, Xin Zheng, Xiao-Qiu Zhou, Wei-Dan Jiang, Yang Liu, Jun Jiang, Sheng-Yao Kuang, Ling Tang, Yong-An Zhang, Lin Feng
The aim of this study was to assess the effects of dietary pyridoxine (PN) deficiency on intestinal antioxidant capacity, cell apoptosis and intercellular tight junction in young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp (231.85 ± 0.63 g) were fed six diets containing graded levels of PN (0.12-7.48 mg/kg diet) for 10 weeks. At the end of the feeding trial, the fish were challenged with Aeromonas hydrophila for 2 weeks. The results showed that compared with the optimal PN level, PN deficiency (1) increased the contents of reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl (PC), decreased the activities and mRNA levels of antioxidant enzymes such as copper, zinc superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR) (P < ...
January 12, 2018: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29336479/inhibition-of-glycolytic-metabolism-in-glioblastoma-cells-by-pt3glc-combinated-with-pi3k-inhibitor-via-sirt3-mediated-mitochondrial-and-pi3k-akt-mapk-pathway
#8
Gang Wang, Xing-Li Fu, Jun-Jie Wang, Rui Guan, Yan Sun, Shing-Shun Tony To
Glioblastoma multiforme (GBM) is the most malignant and aggressive glioma with abnormal expression of genes that mediate glycolytic metabolism and tumor cell growth. Petunidin-3-O- glucoside (Pt3glc) is a kind of anthocyanin in the red grape and derived beverages, representing the most common naturally occurring anthocyanins with a reduced incidence of cancer and heart diseases. In this study, whether Pt3glc could effectively regulate glycolysis to inhibit GBM cell was investigated by using the DBTRG-05MG cell lines...
January 16, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29336467/nox4-ros-mediate-ethanol%C3%A2-induced-apoptosis-via-mapk-signal-pathway-in-l%C3%A2-02-cells
#9
Cheng-Fang Yang, Yu-Juan Zhong, Zuheng Ma, Li Li, Lin Shi, Li Chen, Chen Li, Dan Wu, Qi Chen, Yong-Wen Li
The aim of the present study was to assess the molecular mechanism of ethanol‑induced oxidative stress‑mediated apoptosis in L‑02 liver cells in order to elucidate novel pathways associated with alcoholic liver disease. L‑02 cells were treated with 400 mM ethanol with or without inhibitors. The cell viability was measured by an MTT assay. Cell apoptosis was assessed by flow cytometry and a single‑stranded DNA (ssDNA) assay. Intracellular reactive oxygen species (ROS) production of L‑02 cells was determined using the 2',7'‑dichlorofluorescein‑diacetate dye...
January 16, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29335437/deubiquitinase-usp13-dictates-mcl1-stability-and-sensitivity-to-bh3-mimetic-inhibitors
#10
Shengzhe Zhang, Meiying Zhang, Ying Jing, Xia Yin, Pengfei Ma, Zhenfeng Zhang, Xiaojie Wang, Wen Di, Guanglei Zhuang
MCL1 is a pivot member of the anti-apoptotic BCL-2 family proteins. While a distinctive feature of MCL1 resides in its efficient ubiquitination and destruction, the deubiquitinase USP9X has been implicated in the preservation of MCL1 expression by removing the polyubiquitin chains. Here we perform an unbiased siRNA screen and identify that the second deubiquitinase, USP13, regulates MCL1 stability in lung and ovarian cancer cells. Mechanistically, USP13 interacts with and stabilizes MCL1 via deubiquitination...
January 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29335202/5-bromo-oxoisoaporphine-platinum-ii-complexes-exhibit-tumor-cell-cytotoxcicity-via-inhibition-of-telomerase-activity-and-disruption-of-c-myc-g-quadruplex-dna-and-mitochondrial-functions
#11
Zu-Zhuang Wei, Qi-Pin Qin, Ting Meng, Cai-Xing Deng, Hong Liang, Zhen-Feng Chen
Two platinum(II) complexes [Pt(L)(DMSO)Cl] (1) and [Pt(L)(pn)]Cl (2) with 5-bromo-oxoisoaporphine (H-L) were synthesized. We found that the two new platinum(II) complexes were more selective for Hep-G2 tumor cells than for normal cells (HL-7702, WI-38 and L-o2 cell lines). 5-Bromine-oxoisoaporphine platinum(II) complex 2 was a telomerase inhibitor targeting c-myc G4, and it triggered Hep-G2 cell apoptosis more potently than complex 1. Moreover, they induced cell apoptosis via disruption of mitochondrial functions...
January 4, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29333953/the-irreversible-erbb1-2-4-inhibitor-neratinib-interacts-with-the-bcl-2-inhibitor-venetoclax-to-kill-mammary-cancer-cells
#12
Laurence Booth, Jane L Roberts, Francesca Avogadri-Connors, Richard E CutlerJr, Alshad S Lalani, Andrew Poklepovic, Paul Dent
The irreversible ERBB1/2/4 inhibitor, neratinib, down-regulates the expression of ERBB1/2/4 as well as the levels of MCL-1 and BCL-XL. Venetoclax (ABT199) is a BCL-2 inhibitor. At physiologic concentrations neratinib interacted in a synergistic fashion with venetoclax to kill HER2+ and TNBC mammary carcinoma cells. This was associated with the drug-combination: reducing the expression and phosphorylation of ERBB1/2/3; in an eIF2α-dependent fashion reducing the expression of MCL-1 and BCL-XL and increasing the expression of Beclin1 and ATG5; and increasing the activity of the ATM-AMPKα-ULK1 S317 pathway which was causal in the formation of toxic autophagosomes...
January 15, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29333604/adiponectin-inhibits-inflammatory-cytokines-production-by-beclin-1-phosphorylation-and-bcl-2-mrna-destabilization-role-for-autophagy-induction
#13
Nirmala Tilija Pun, Pil-Hoon Park
BACKGROUND AND PURPOSE: Adiponectin potently suppresses inflammatory mediator production. Autophagy is known to play a critical role in modulating inflammatory responses by adiponectin. However, the underlying mechanisms are not clearly understood. Interaction between Beclin-1 and Bcl-2 is a critical event in autophagy induction. We examined the effects of globular adiponectin (gAcrp) on the Beclin-1/Bcl-2 association and its underlying mechanisms. EXPERIMENTAL APPROACH: The effect of gAcrp on the interaction between Beclin-1 and Bcl-2 was examined by immunoprecipitation followed by Western blotting...
January 14, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29331104/inhibition-of-mircorna-34a-enhances-survival-of-human-bone-marrow-mesenchymal-stromal-stem-cells-under-oxidative-stress
#14
Yang Liu, Xiaohu Zhang, Jie Chen, Tingyu Li
BACKGROUND Mesenchymal stromal/stem cells (MSCs) are broadly used for many diseases, but the efficacy of MSC engraftment is very low due to low viability and high cell death rate under a stressful microenvironment. The present study aimed to investigate whether microRNA-34a (miR-34a), which is a downstream target of P53, is involved in H2O2-induced MSC cell death. MATERIAL AND METHODS Human bone marrow MSCs (hMSCs) were purchased from Lonza and were cultured as previously described. hMSCs were transfected with miR-34a inhibitor and exposed to H2O2...
January 13, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29328455/role-of-mir-21-in-the-growth-and-metastasis-of-human-salivary-adenoid-cystic-carcinoma
#15
Fei Yan, Chao Wang, Ting Li, Wenyan Cai, Jinhu Sun
Aberrant microRNA (miRNA/miR) expression has been reported in various cancer types. miR‑21, which is considered to be a proto-oncogene and is frequently overexpressed in certain cancer types, has been implicated in tumorigenesis. The aim of the present study was to investigate the effect of miR‑21 degradation on tumor progression and its potential mechanisms in human salivary adenoid cystic carcinoma (SACC) development. Results of reverse transcription‑quantitative polymerase chain reaction analysis indicated that SACC cells with high metastatic potential (SACC‑LM cells) exhibited a significantly higher expression of miR‑21 compared with SACC cells with a lower metastatic potential (SACC‑83 cells)...
January 5, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29328450/mybl2-protects-against-h9c2-injury-induced-by-hypoxia-via-akt-and-nf%C3%A2-%C3%AE%C2%BAb-pathways
#16
Mingfeng Shao, Zexiang Ren, Rongjun Zhang
Cardiovascular diseases have become one of the major public health problems in many countries. The downregulation of MYBL2 was found in H9c2 and native cardiomyocytes cells after hypoxia treatment. The present study aimed to investigate the effects of MYB proto‑oncogene like 2 (MYBL2) on H9c2 injury induced by hypoxia. Reverse transcription‑quantitative polymerase chain reaction and western blot were performed on H9c2 cells to determine the mRNA and protein levels of MYBL2, respectively. Small interfering RNA (siRNA) was employed to downregulate MYBL2 expression in H9c2 cells to investigate changes in cell proliferation and apoptosis...
January 8, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29328387/rhus-verniciflua-stokes-extract-induces-inhibition-of-cell-growth-and-apoptosis-in-human-chronic-myelogenous-leukemia-k562-cells
#17
Kyung-Wook Lee, Eun-Sik Um, Bo-Bae Jung, Eun-Sol Choi, Eun-Young Kim, Seungbo Lee, Eungyeong Jang, Jang-Hoon Lee, Youngchul Kim
Rhus verniciflua Stokes has been widely used as a traditional medicinal plant with a variety of pharmacological activities. We investigated the mechanisms involved in mediating the effects of Rhus verniciflua Strokes (R. verniciflua) extract in human chronic myelogenous leukemia K562 cells, including caspase-dependent apoptotic pathways related to cell-cycle arrest, as well as the inhibition of nuclear factor NF-κB activation and upregulation of the mitogen-activated protein kinase (MAPK) signaling pathway...
January 3, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29324310/25-hydroxyl-protopanaxatriol-protects-against-h2o2-induced-h9c2-cardiomyocytes-injury-via-pi3k-akt-pathway-and-apoptotic-protein-down-regulation
#18
Zhihao Wang, Guangyue Su, Zhiguo Zhang, Han Dong, Yuehui Wang, Huiying Zhao, Yuqing Zhao, Qi Sun
Oxidative stress injury and apoptosis are the main mechanisms of myocardial ischemia-reperfusion injury (MI/RI). Compounds with anti-oxidant properties can treat MI/RI. Therefore, identification of natural antioxidants such as herbs or botanical drugs is an ideal strategy to develop safe and effective anti-MI/RI drugs. Cardioprotective effects of Ginseng are well documented and are attributable to its anti-oxidant, anti-inflammatory, anti-tumorigenic, anti-arrhythmic, anti-ischemic properties. Ginseng monomer 20®-dammarane -3 beta,6 alpha,12 beta,20,25-pentol(25-hydroxyl-Protopanaxatriol,25-OH-PPT), a novel compound, which belongs to panaxatriol category, is extracted from the leaves and stem of ginseng...
January 8, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29323899/optimization-of-potent-and-selective-tricyclic-indole-diazepinone-myeloid-cell-leukemia-1-mcl-1-inhibitors-using-structure-based-design
#19
Subrata Shaw, Zhiguo Bian, Bin Zhao, James C Tarr, Nagarathanam Veerasamy, KyuOk Jeon, Johannes Belmar, Allison L Arnold, Stuart A Fogarty, Evan Perry, John L Sensintaffar, DeMarco V Camper, Olivia W Rossanese, Taekyu Lee, Edward T Olejniczak, Stephen W Fesik
Myeloid cell leukemia 1 (Mcl-1), an anti-apoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1 sensitive cells...
January 11, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29323257/dengue-virus-induced-er-stress-is-required-for-autophagy-activation-viral-replication-and-pathogenesis-both-in-vitro-and-in-vivo
#20
Ying-Ray Lee, Szu-Han Kuo, Ching-Yen Lin, Po-Jung Fu, Yee-Shin Lin, Trai-Ming Yeh, Hsiao-Sheng Liu
Dengue virus (DENV) utilizes the endoplasmic reticulum (ER) for replication and assembling. Accumulation of unfolded proteins in the ER lumen leads to ER stress and unfolded protein response (UPR). Three branches of UPRs temporally modulated DENV infection. Moreover, ER stress can also induce autophagy. DENV infection induces autophagy which plays a promotive role in viral replication has been reported. However, the role of ER stress in DENV-induced autophagy, viral titer, and pathogenesis remain unclear. Here, we reveal that ER stress and its downstream UPRs are indispensable for DENV-induced autophagy in various human cells...
January 11, 2018: Scientific Reports
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