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Bcl-2 family proteins

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https://www.readbyqxmd.com/read/28735187/progress-in-targeting-the-bcl-2-family-of-proteins
#1
REVIEW
Thomas P Garner, Andrea Lopez, Denis E Reyna, Adam Z Spitz, Evripidis Gavathiotis
The network of protein-protein interactions among the BCL-2 protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Anti-apoptotic BCL-2 proteins are considered promising targets for drug discovery and exciting clinical progress has stimulated intense investigations in the broader family. Here, we discuss recent developments in small molecules targeting anti-apoptotic proteins and alternative approaches to targeting BCL-2 family interactions. These studies advance our understanding of the role of BCL-2 family proteins in physiology and disease, providing unique tools for dissecting these functions...
July 20, 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28730425/at-101-acts-as-anti-proliferative-and-hormone-suppressive-agent-in-mouse-pituitary-corticotroph-tumor-cells
#2
B S Yurekli, B Karaca, A Kisim, E Bozkurt, H Atmaca, S Cetinkalp, G Ozgen, C Yilmaz, S Uzunoglu, R Uslu, F Saygili
PURPOSE: Gossypol, a naturally occurring compound in cottonseeds, has anticancer effects against several tumor cell lines. It has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R (-)-gossypol, binds to Bcl-2 family proteins and induces apoptosis in vitro. Although transsphenoidal surgical excision of the pituitary corticotroph adenoma is the gold standard of care, it is not successful all the time. Medical therapy for Cushing's disease still remains a challenge for the clinicians...
July 20, 2017: Journal of Endocrinological Investigation
https://www.readbyqxmd.com/read/28729093/pim-kinases-1-2-and-3-in-intracellular-lif-signalling-proliferation-and-apoptosis-in-trophoblastic-cells
#3
Stella Mary Photini, Wittaya Chaiwangyen, Maja Weber, Boodor Al-Kawlani, Rodolfo R Favaro, Udo Jeschke, Ekkehard Schleussner, Diana M Morales-Prieto, Udo R Markert
Proviral insertion in murine (PIM) lymphoma proteins are mainly regulated by the Janus Kinase/Signal Transducer Activator of Transcription (JAK/STAT) signaling pathway, which can be activated by members of the Interleukin-6 (IL-6) family, including Leukemia Inhibitory Factor (LIF). Aim of the study was to compare PIM1, PIM2 and PIM3 expression and potential cellular functions in human first and third trimester trophoblast cells, the immortalized first trimester extravillous trophoblast cell line HTR8/SVneo and the choriocarcinoma cell line JEG-3...
July 17, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28724540/targeting-bcl-2-in-b-cell-lymphomas
#4
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, yet several early attempts to target this pathway therapeutically were unsuccessful due to toxicity, lack of efficacy, or both. Recently, a highly potent and selective oral BCL-2 antagonist, venetoclax, was approved in chronic lymphocytic leukemia (CLL), where it has proven to be highly active, even in patients with high risk del(17p) disease...
July 19, 2017: Blood
https://www.readbyqxmd.com/read/28718669/fruit-peel-polyphenolic-extract-induced-apoptosis-in-human-breast-cancer-cells-is-associated-with-ros-production-and-modulation-of-p38mapk-erk1-2-and-the-akt-signaling-pathway
#5
Martin Kello, Lucia Kulikova, Janka Vaskova, Alexandra Nagyova, Jan Mojzis
Polyphenols represent a large group of natural substances with different biological properties. Currently, polyphenols are well studied due to their free radicals' scavenging and antioxidant activities. However, some studies indicate that polyphenols also exhibit pro-oxidant properties. In this study, the possible involvement of the pro-oxidant activities of fruit polyphenols was investigated in relation to apoptosis induction. To determine the type of cell death induced by fruit polyphenols (Flavine; F7), we assessed a series of assays, including measurements of caspase-7 activation, membrane mitochondrial potential changes, reactive oxygen (ROS) and nitrogen species production, lipid peroxidation, antioxidant enzymes activities, and PARP cleavage...
July 18, 2017: Nutrition and Cancer
https://www.readbyqxmd.com/read/28717011/dysregulation-of-bcl-2-family-proteins-by-leukaemia-fusion-genes
#6
Lauren M Brown, Diane T Hanna, Seong L Khaw, Paul G Ekert
The genomic lesions that characterise acute lymphoblastic leukaemia in childhood include recurrent translocations that result in the expression of fusion proteins. These translocations typically involve the rearrangement of genes encoding tyrosine kinases, including receptor tyrosine kinase, cytokine receptors and transcription factors. These confer phenotypic changes that are the hallmarks of malignant transformation, including unrestricted proliferation and a relative resistance to apoptosis. In this review, we explore the molecular mechanisms that link these fusions to the control of cell death...
July 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28714472/targeting-the-differential-addiction-to-anti-apoptotic-bcl-2-family-for-cancer-therapy
#7
Akane Inoue-Yamauchi, Paul S Jeng, Kwanghee Kim, Hui-Chen Chen, Song Han, Yogesh Tengarai Ganesan, Kota Ishizawa, Sylvia Jebiwott, Yiyu Dong, Maria C Pietanza, Matthew D Hellmann, Mark G Kris, James J Hsieh, Emily H Cheng
BCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263...
July 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28713991/pien-tze-huang-gan-bao-attenuates-carbon-tetrachloride%C3%A2-induced-hepatocyte-apoptosis-in-rats-associated-with-suppression-of-p53-activation-and-oxidative-stress
#8
Jinyan Zhao, Yuchen Zhang, Yun Wan, Haixia Hu, Zhenfeng Hong
Pien Tze Huang Gan Bao (PZH‑GB), a traditional Chinese medicine, has been used for thousands of years as a protective remedy effective against liver injury induced by excessive alcohol and smoking. The present study aimed to evaluate the protective effects and potential mechanisms of PZH‑GB against carbon tetrachloride (CCl4)‑induced hepatic injury. Rats were pre‑treated with silymarin (50 mg/kg) or different doses of PZH‑GB (150, 300 or 600 mg/kg) orally administered for 7 days. At the end of treatment, the rats were intraperitoneally injected with CCl4, or control rats received a corn oil injection...
July 6, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28713289/mitochondrial-vdac1-a-key-gatekeeper-as-potential-therapeutic-target
#9
REVIEW
Amadou K S Camara, YiFan Zhou, Po-Chao Wen, Emad Tajkhorshid, Wai-Meng Kwok
Mitochondria are the key source of ATP that fuels cellular functions, and they are also central in cellular signaling, cell division and apoptosis. Dysfunction of mitochondria has been implicated in a wide range of diseases, including neurodegenerative and cardiac diseases, and various types of cancer. One of the key proteins that regulate mitochondrial function is the voltage-dependent anion channel 1 (VDAC1), the most abundant protein on the outer membrane of mitochondria. VDAC1 is the gatekeeper for the passages of metabolites, nucleotides, and ions; it plays a crucial role in regulating apoptosis due to its interaction with apoptotic and anti-apoptotic proteins, namely members of the Bcl-2 family of proteins and hexokinase...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28713162/abt-263-induces-g1-g0-phase-arrest-apoptosis-and-autophagy-in-human-esophageal-cancer-cells-in-vitro
#10
Qing-Huan Lin, Fu-Chang Que, Chun-Ping Gu, De-Sheng Zhong, Dan Zhou, Yi Kong, Le Yu, Shu-Wen Liu
Both the anti- and pro-apoptotic members of the Bcl-2 family are regulated by a conserved Bcl-2 homology (BH3) domain. ABT-263 (Navitoclax), a novel BH3 mimetic and orally bioavailable Bcl-2 family inhibitor with high affinity for Bcl-xL, Bcl-2 and Bcl-w has entered clinical trials for cancer treatment. But the anticancer mechanisms of ABT-263 have not been fully elucidated. In this study we investigated the effects of ABT-263 on human esophageal cancer cells in vitro and to explore its anticancer mechanisms...
July 17, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28712506/vdac1-functions-in-ca-2-homeostasis-and-cell-life-and-death-in-health-and-disease
#11
REVIEW
Varda Shoshan-Barmatz, Yakov Krelin, Anna Shteinfer-Kuzmine
In the outer mitochondrial membrane (OMM), the voltage-dependent anion channel 1 (VDAC1) serves as a mitochondrial gatekeeper, controlling the metabolic and energy cross-talk between mitochondria and the rest of the cell. VDAC1 also functions in cellular Ca(2+) homeostasis by transporting Ca(2+) in and out of mitochondria. VDAC1 has also been recognized as a key protein in mitochondria-mediated apoptosis, contributing to the release of apoptotic proteins located in the inter-membranal space (IMS) and regulating apoptosis via association with pro- and anti-apoptotic members of the Bcl-2 family of proteins and hexokinase...
June 23, 2017: Cell Calcium
https://www.readbyqxmd.com/read/28712306/targeting-intrinsic-apoptosis-and-other-forms-of-cell-death-by-bh3-mimetics-in-glioblastoma
#12
Georg Karpel-Massler, Chiaki Tsuge Ishida, Yiru Zhang, Marc-Eric Halatsch, M-Andrew Westhoff, Markus D Siegelin
Novel approaches to treat malignant brain tumors are necessary since these neoplasms still display an unfavorable prognosis. Areas covered: In this review, the authors summarize and analyze recent preclinical data that suggest that targeting intrinsic apoptosis may be a suitable strategy for the treatment of malignant gliomas. They focus on the anti-apoptotic Bcl-2 family members of proteins and the recent drug developments in that field with a special focus on BH3-mimetics. With the discovery of BH3-mimetics that interfere with anti-apoptotic Bcl-2 family members in the low nanomolar range significant excitement has been generated towards these class of inhibitors, such as ABT-737, ABT-263 and the most recent successor, ABT-199 which is most advanced with respect to clinical application...
July 17, 2017: Expert Opinion on Drug Discovery
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
#13
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/28708509/gdf8-activates-p38-mapk-signaling-during-porcine-oocyte-maturation-in%C3%A2-vitro
#14
Junchul David Yoon, Seon-Ung Hwang, Eunhye Kim, Minghui Jin, Soochong Kim, Sang-Hwan Hyun
Growth Differentiation Factor 8 (GDF8) is a member of the transforming growth factor-β (TGF-β) family and has been identified as a strong physiological regulator. This factor is expressed as a paracrine factor in mural granulosa cells. To investigate the effects of GDF8 on the in vitro maturation (IVM) of porcine oocytes, we assessed the quality of matured oocytes as well as the specific gene transcription and protein activation levels in oocytes and cumulus cells (CCs) after IVM and subsequent embryonic development after in vitro fertilization (IVF) and parthenogenetic activation (PA)...
June 6, 2017: Theriogenology
https://www.readbyqxmd.com/read/28706417/indole-phytoalexin-derivatives-induce-mitochondrial-mediated-apoptosis-in-human-colorectal-carcinoma-cells
#15
Viera Tischlerova, Martin Kello, Mariana Budovska, Jan Mojzis
AIM: To investigate the mechanism of the antiproliferative effect of synthetic indole phytoalexin derivatives on human colorectal cancer cell lines. METHODS: Changes in cell proliferation and the cytotoxic effect of the tested compounds on human colorectal cancer cell lines and human fibroblasts were evaluated using MTS and BrdU assay, allowing us to choose the most potent substance. Cell cycle alterations were analyzed using flow cytometric analysis. The apoptosis-inducing effect of compound K-453 on the HCT116 cell line was examined with annexin V/PI double staining using flow cytometry, as well as acridine orange/propidium iodide (AO/PI) staining...
June 28, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28706229/quantitative-interactome-of-a-membrane-bcl-2-network-identifies-a-hierarchy-of-complexes-for-apoptosis-regulation
#16
Stephanie Bleicken, Annika Hantusch, Kushal Kumar Das, Tancred Frickey, Ana J Garcia-Saez
The Bcl-2 proteins form a complex interaction network that controls mitochondrial permeabilization and apoptosis. The relative importance of different Bcl-2 complexes and their spatio-temporal regulation is debated. Using fluorescence cross-correlation spectroscopy to quantify the interactions within a minimal Bcl-2 network, comprised by cBid, Bax, and Bcl-xL, we show that membrane insertion drastically alters the pattern of Bcl-2 complexes, and that the C-terminal helix of Bcl-xL determines its binding preferences...
July 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28705421/bcl-2-inhibitors-as-anti-cancer-therapeutics-the-impact-of-and-on-calcium-signaling
#17
REVIEW
Tamara Vervloessem, Martijn Kerkhofs, Rita M La Rovere, Flore Sneyers, Jan B Parys, Geert Bultynck
Bcl-2-protein family members are essential regulators of apoptosis. Anti-apoptotic Bcl-2 proteins ensure cell survival via different mechanisms, including via binding of pro-apoptotic Bcl-2-family members and the modulation of intracellular Ca(2+)-transport systems. Many cancer cells upregulate these proteins to overcome the consequences of ongoing oncogenic stress. Bcl-2 inhibition leading to cell death, therefore emerged as a novel cancer therapy. Different Bcl-2 inhibitors have already been developed including the hydrophobic cleft-targeting BH3 mimetics, which antagonize Bcl-2's ability to scaffold and neutralize pro-apoptotic Bcl-2-family members...
June 4, 2017: Cell Calcium
https://www.readbyqxmd.com/read/28700107/cigarette-smoke-induces-rat-testicular-injury-via-mitochondrial-apoptotic-pathway
#18
He Lijuan, You Shuping, Gong Haiyan, Zhang Jing, Wang Li, Zhang Chen, Huang Yunfei, Zhong Chunxue, Zou Ying
An understanding of the causative mechanisms of the harmful effects of cigarette smoke on the male reproductive system remains incomplete. Here, we investigated three different inhaled cigarette smoke doses over five different exposure durations to identify how the testis is affected. The effects of cigarette smoke exposure on testicular germ cells were characterized by morphological changes and a significant elevation in the number of apoptotic cells. Caspase 3 activation increased dramatically after cigarette smoke exposure, accompanied by significant time-dependent expression of the pro-apoptotic proteins Bak (B cell lymphoma/leukemia 2 [Bcl-2] homologous antagonist killer), Bcl2l11 (a BH3 domain-only protein related to Bcl-2), Apaf1 (Apoptotic protease-activating factor-1), and Caspase 9...
July 12, 2017: Molecular Reproduction and Development
https://www.readbyqxmd.com/read/28696828/small-molecule-inhibitor-tw-37-is-tolerable-and-synergistic-with-chemotherapy-in-nasopharyngeal-carcinoma
#19
Ying Lu, Haixin Huang, Hui Yang, Dagui Chen, Sibei Wu, Zhou Jiang, Rensheng Wang
Chemotherapy is a crucial adjuvant therapy of advanced nasopharyngeal carcinoma (NPC). However, enhancing sensitivity and tolerance of chemotherapeutics in NPC treatment have been challenging. Both Bcl-2 and Mcl-1, 2 pro-survival proteins of Bcl-2 family, play essential roles on the chemotherapy tolerance of numerous cancers. In the present study, we explored the influences of TW-37, a small molecule inhibitor of Bcl-2 and Mcl-1, on the efficiency of chemotherapy for NPC. Oncomine cancer database shows that NPC tissues have higher expression of Bcl-2 and Mcl-1 than those of normal nasopharyngeal epithelial (NPE) tissues...
July 11, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28689004/the-role-of-succinate-and-ros-in-reperfusion-injury-a-critical-appraisal
#20
REVIEW
Tatyana N Andrienko, Philippe Pasdois, Gonçalo C Pereira, Matthew J Ovens, Andrew P Halestrap
We critically assess the proposal that succinate-fuelled reverse electron flow (REF) drives mitochondrial matrix superoxide production from Complex I early in reperfusion, thus acting as a key mediator of ischemia/reperfusion (IR) injury. Real-time surface fluorescence measurements of NAD(P)H and flavoprotein redox state suggest that conditions are unfavourable for REF during early reperfusion. Furthermore, rapid loss of succinate accumulated during ischemia can be explained by its efflux rather than oxidation...
July 5, 2017: Journal of Molecular and Cellular Cardiology
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