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Bcl-2 inhibitors

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https://www.readbyqxmd.com/read/29340082/reciprocal-sensitivity-of-diffuse-large-b-cell-lymphoma-cells-to-bcl-2-inhibitors-bird-2-versus-venetoclax
#1
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/29340070/a-novel-orally-available-syk-src-jak2-inhibitor-sklb-850-showed-potent-anti-tumor-activities-in-b-cell-lymphoma-bcl-models
#2
Nannan Zhang, Guo Zhang, Ning Liu, Wanting Lin, Sen Ji, Mingwu Zheng, Kai Chen, Xiao Liang, Guobo Li, Yu Ma, Jun Zhu, Ting Niu, Lin-Li Li, Jiong Li, Yu-Quan Wei, Sheng-Yong Yang
B cell lymphoma (BCL) is the most frequently diagnosed type of non-Hodgkin lymphoma (NHL), and accounts for about 4% of all cancers in the USA. Kinases spleen tyrosine kinase (Syk), Src, and Janus kinase 2 (JAK2) have been thought as potential targets for the treatment of BCL. We have recently developed a multikinase inhibitor, SKLB-850, which potently inhibits Syk, Src, and JAK2. The aim of this study is to investigate the anti-BCL activities and mechanisms of action of SKLB-850 both in vitro and in vivo. Our results showed that SKLB-850 significantly inhibited BCL cell proliferation, and induced apoptosis of BCL cells...
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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/29333957/mir-98-promotes-apoptosis-of-glioma-cells-via-suppressing-ikbke-nf-%C3%AE%C2%BAb-pathway
#9
Lingyan Wang, Shaolei Guo, Heng Zhang
The inhibitor of kappa B kinase epsilon is overexpressed in glioma and plays antiapoptotic role via activating nuclear factor-kappa B. microRNA-98 can suppress glioma, modulate the activities of nuclear factor-kappa B, and bind to the 3'-untranslated region of inhibitor of kappa B kinase epsilon messenger RNA. This study was aimed to investigate the modulation of inhibitor of kappa B kinase epsilon/nuclear factor-kappa B by microRNA-98 in glioma. The results indicated that microRNA-98 was downregulated in glioma cell lines and human glioma tissues...
December 2017: Technology in Cancer Research & Treatment
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
#10
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
#11
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/29333561/pharmacokinetics-of-the-b-cell-lymphoma-2-bcl-2-inhibitor-venetoclax-in-female-subjects-with-systemic-lupus-erythematosus
#12
Mukul Minocha, Jiewei Zeng, Jeroen K Medema, Ahmed A Othman
BACKGROUND AND OBJECTIVE: Venetoclax is an oral selective Bcl-2 inhibitor approved for the treatment of patients with chronic lymphocytic leukemia with 17p deletion. Mechanistic and preclinical evidence warranted evaluation of venetoclax for the treatment of systemic lupus erythematosus (SLE). This work characterized the pharmacokinetics of venetoclax in female subjects with SLE. METHODS: Single (10-500 mg) and multiple (30-600 mg) escalating doses of venetoclax or matching placebo were evaluated using randomized, double-blind, placebo-controlled designs (6 active and 2 placebo per dose with 73 unique SLE patients enrolled, 25 of whom enrolled twice)...
January 15, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29331104/inhibition-of-mircorna-34a-enhances-survival-of-human-bone-marrow-mesenchymal-stromal-stem-cells-under-oxidative-stress
#13
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/29329659/discovery-of-mcl-1-inhibitors-based-on-a-thiazolidine-2-4-dione-scaffold
#14
Ellis Whiting, Mithun R Raje, Jay Chauhan, Paul T Wilder, Daniel Van Eker, Samuel J Hughes, Nathan G Bowen, Gregory E A Vickers, Ian C Fenimore, Steven Fletcher
Inspired by a rhodanine-based dual inhibitor of Bcl-xL and Mcl-1, a focused library of analogues was prepared wherein the rhodanine core was replaced with a less promiscuous thiazolidine-2,4-dione scaffold. Compounds were initially evaluated for their abilities to inhibit Mcl-1. The most potent compound 12b inhibited Mcl-1 with a Ki of 155 nM. Further investigation revealed comparable inhibition of Bcl-xL (Ki = 90 nM), indicating that the dual inhibitory profile of the initial rhodanine lead had been retained upon switching the heterocycle core...
December 12, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29329609/garcinia-xanthochymus-extract-protects-pc12-cells-from-h2o2-induced-apoptosis-through-modulation-of-pi3k-akt-and-nrf2-ho-1-pathways
#15
Jing Xu, Sheng Gan, Jun Li, De-Bing Wand, Yu Chen, Xin Hu, Guang-Zhong Yang
The aim of the present study was to investigate the protective effects and underlying mechanisms of Garcinia xanthochymus, a perennial medicinal plant native to Yunnan, China, against H2O2-induced oxidative damage in rat pheochromacytoma PC12 cells. Preincubation of PC12 cells with fruit EtOAc fraction (fruit-EFr., 12.5-50 µmol·L-1) of G. xanthochymus for 24 h prior to H2O2 exposure markedly improved cell viability and increased the activities of antioxidant enzymes (superoxide dismutase, catalase, and heme oxygenase-1 [HO-1]), prevented lactate dehydrogenase release and lipid peroxidation malondialdehyde production, attenuated the decrease of matrix metalloproteinases (MMP), and scavenged reactive oxygen species (ROS)...
November 2017: Chinese Journal of Natural Medicines
https://www.readbyqxmd.com/read/29328455/role-of-mir-21-in-the-growth-and-metastasis-of-human-salivary-adenoid-cystic-carcinoma
#16
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
#17
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
#18
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
#19
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
#20
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
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