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https://www.readbyqxmd.com/read/27919962/ascorbyl-stearate-promotes-apoptosis-through-intrinsic-mitochondrial-pathway-in-hela-cancer-cells
#1
Shirish D Mane, Maikho Thoh, Deepak Sharma, Santosh K Sandur, K Akhilender Naidu
BACKGROUND: Ascorbic acid is proposed to have antitumor potential against certain cancer types but has the limitation of requiring high doses for treating cancer. Ascorbyl stearate (ASC-S) is a fatty acid ester derivative of ascorbic acid with comparable potent apoptotic activity. The present study was aimed at understanding the pathway involved in apoptotic activity of ASC-S in cervical cancer cells. MATERIALS AND METHODS: The effect of ASC-S on reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) was studied in HeLa cells...
December 2016: Anticancer Research
https://www.readbyqxmd.com/read/27913204/the-selective-bcl-2-inhibitor-venetoclax-a-bh3-mimetic-does-not-dysregulate-intracellular-ca-2-signaling
#2
Tamara Vervloessem, Hristina Ivanova, Tomas Luyten, Jan B Parys, Geert Bultynck
Anti-apoptotic B cell-lymphoma-2 (Bcl-2) proteins are emerging as therapeutic targets in a variety of cancers for precision medicines, like the BH3-mimetic drug venetoclax (ABT-199), which antagonizes the hydrophobic cleft of Bcl-2. However, the impact of venetoclax on intracellular Ca(2+) homeostasis and dynamics in cell systems has not been characterized in detail. Here, we show that venetoclax did not affect Ca(2+)-transport systems from the endoplasmic reticulum (ER) in permeabilized cell systems. Venetoclax (1μM) did neither trigger Ca(2+) release by itself nor affect agonist-induced Ca(2+) release in a variety of intact cell models...
November 29, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27911011/fragment-based-design-synthesis-and-biological-evaluation-of-1-substituted-indole-2-carboxylic-acids-as-selective-mcl-1-inhibitors
#3
Ziqian Wang, Wenjie Xu, Ting Song, Zongwei Guo, Lu Liu, Yudan Fan, Anhui Wang, Zhichao Zhang
Based on a known selective Mcl-1 inhibitor, 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid, we applied a fragment-based approach to obtain new molecules that extended into the p1 pocket of the BH3 groove and then exhibited binding selectivity for the Mcl-1 over the Bcl-2 protein. After we deconstructed the 1H-indole-2-carboxylic acid from the parental molecule, a benzenesulfonyl was substituted at the 1-position to adopt a geometry preferred for accessing the p1 pocket according to the binding mode of the parental molecule identified by X-ray crystallography...
December 2, 2016: Archiv der Pharmazie
https://www.readbyqxmd.com/read/27905446/genomic-evolution-and-chemoresistance-in-germ-cell-tumours
#4
Amaro Taylor-Weiner, Travis Zack, Elizabeth O'Donnell, Jennifer L Guerriero, Brandon Bernard, Anita Reddy, G Celine Han, Saud AlDubayan, Ali Amin-Mansour, Steven E Schumacher, Kevin Litchfield, Clare Turnbull, Stacey Gabriel, Rameen Beroukhim, Gad Getz, Scott L Carter, Michelle S Hirsch, Anthony Letai, Christopher Sweeney, Eliezer M Van Allen
Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes. GCTs are histologically heterogeneous and distinctly curable with chemotherapy. Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs, but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types...
November 30, 2016: Nature
https://www.readbyqxmd.com/read/27900790/revealing-germylene-compounds-to-attain-superbasicity-with-sigma-donor-substituents-a-density-functional-theory-study
#5
Bishwajit Ganguly, Abul Kalam Biswas
This study reports for the first time that compounds of Ge (II) can function as superbases. Two B(N=PiPr3)2 groups attached to a germanium (II) center show a gas phase proton affinity of 296.2 kcal/mol, close to the range of a hyperbase as revealed by B3LYP-D3/6-31G(2d,p) level of theory. These DFT calculations showed better agreement of geometrical parameters for the reported stable germylene compound 1 than previously reported calculations at the B3LYP/6-31G(2d,p) and PBE/DZP level of theory. A systematic study performed with different substitutions of Ge(II) revealed that such system can achieve basicity close to a hyperbase...
November 30, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27895791/nedaplatin-enhanced-apoptotic-effects-of-abt-737-in-human-cancer-cells-via-mcl-1-inhibition
#6
Chong Zhang, Yang-Ling Li, Xu Weng, Li-Yan Li, Ming-Xian Zhou, Da-Yong Zhang, Neng-Ming Lin
Platinum compounds, such as cisplatin, carboplatin, oxaliplatin and nedaplatin, are widely used to treat a number of solid malignancies. Nedaplatin is a second-generation platinum complex, based on its pronounced anti-cancer activities against several solid tumors being equivalent to that of cisplatin, but with lower nephrotoxicity. In this context, the present study aimed to investigate the potential anti-cancer effect by combining nedaplatin with ABT-737. It was found that nedaplatin greatly increased ABT-737-mediated apoptosis in A549 and 95-D cells, accompanied by enhanced cleavage of poly(ADP-ribose) polymerase and caspase-3...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27890930/histone-deacetylase-inhibitors-interrupt-hsp90-rasgrp1-and-hsp90-craf-interactions-to-upregulate-bim-and-circumvent-drug-resistance-in-lymphoma-cells
#7
H Ding, K L Peterson, C Correia, B Koh, P A Schneider, G S Nowakowski, S H Kaufmann
Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill susceptible cells is incompletely understood. Here we show that trichostatin A, romidepsin, and panobinostat induce apoptosis across a panel of malignant B cell lines, including lines that are intrinsically resistant to bortezomib, etoposide, cytarabine, and BH3 mimetics. Further analysis traces the pro-apoptotic effects of HDAC inhibitors to increased acetylation of the chaperone heat shock protein 90 (HSP90), causing release and degradation of the HSP90 client proteins RASGRP1 and CRAF, which in turn leads to downregulation of mitogen activated protein kinase pathway signaling and upregulation of the pro-apoptotic BCL2 family member BIM in vitro and in vivo...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27889784/targeted-therapy-of-cll
#8
Othman Al-Sawaf, Kirsten Fischer, Barbara Eichhorst, Michael Hallek
The landscape of chronic lymphocytic leukemia (CLL) has undergone profound changes in the past years. First, the addition of CD20-targeting antibodies to conventional chemotherapy has improved the therapeutic outcome in the majority of CLL patients. Since the establishment of the critical role of the B cell receptor signaling pathway in the pathogenesis of CLL, several agents have been developed to target this pathway. Ibrutinib and idelalisib, 2 potent kinase inhibitors, have both become available for CLL therapy in the first and second line...
2016: Oncology Research and Treatment
https://www.readbyqxmd.com/read/27879976/correction-downsizing-the-bad-bh3-peptide-to-small-constrained-%C3%AE-helices-with-improved-ligand-efficiency
#9
Nicholas E Shepherd, Rosemary S Harrison, Gloria Ruiz-Gomez, Giovanni Abbenante, Jody M Mason, David P Fairlie
Correction for 'Downsizing the BAD BH3 peptide to small constrained α-helices with improved ligand efficiency' by Nicholas E. Shepherd et al., Org. Biomol. Chem., 2016, DOI: 10.1039/c6ob02185a.
November 23, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27872497/bcl-2-protein-family-expression-pattern-determines-synergistic-pro-apoptotic-effects-of-bh3-mimetics-with-hemisynthetic-cardiac-glycoside-unbs1450-in-acute-myeloid-leukemia
#10
C Cerella, A Gaigneaux, A Mazumder, J-Y Lee, E Saland, F Radogna, T Farge, F Vergez, C Récher, J-E Sarry, K-W Kim, H Y Shin, M Dicato, M Diederich
Leukemia accepted article preview online, 22 November 2016. doi:10.1038/leu.2016.341.
November 22, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27862899/pro-apoptotic-noxa-is-involved-in-ablative-focal-irradiation-induced-lung-injury
#11
Jee-Youn Kim, Yong-Min An, Won Hoon Choi, Jin-Mo Kim, Samju Cho, Byung Rok Yoo, Jeong Wook Kang, Yun-Sil Lee, Yoon-Jin Lee, Jaeho Cho
Although lung injury including fibrosis is a well-documented side effect of lung irradiation, the mechanisms underlying its pathology are poorly understood. X-rays are known to cause apoptosis in the alveolar epithelial cells of irradiated lungs, which results in fibrosis due to the proliferation and differentiation of fibroblasts and the deposition of collagen. Apoptosis and BH3-only pro-apoptotic proteins have been implicated in the pathogenesis of pulmonary fibrosis. Recently, we have established a clinically analogous experimental model that reflects focal high-dose irradiation of the ipsilateral lung...
November 15, 2016: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/27852038/transcriptomic-metabolomic-reprogramming-in-egfr-mutant-nsclc-early-adaptive-drug-escape-linking-tgf%C3%AE-2-bioenergetics-mitochondrial-priming
#12
Praveena S Thiagarajan, Xiaoliang Wu, Wei Zhang, Ivy Shi, Rakesh Bagai, Patrick Leahy, Yan Feng, Martina Veigl, Daniel Lindner, David Danielpour, Lihong Yin, Rafael Rosell, Trever G Bivona, Zhenfeng Zhang, Patrick C Ma
The impact of EGFR-mutant NSCLC precision therapy is limited by acquired resistance despite initial excellent response. Classic studies of EGFR-mutant clinical resistance to precision therapy were based on tumor rebiopsies late during clinical tumor progression on therapy. Here, we characterized a novel non-mutational early adaptive drug-escape in EGFR-mutant lung tumor cells only days after therapy initiation, that is MET-independent. The drug-escape cell states were analyzed by integrated transcriptomic and metabolomics profiling uncovering a central role for autocrine TGFβ2 in mediating cellular plasticity through profound cellular adaptive Omics reprogramming, with common mechanistic link to prosurvival mitochondrial priming...
November 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27843137/pi3k%C3%AE-inhibition-elicits-anti-leukemic-effects-through-bim-dependent-apoptosis
#13
M J Carter, K L Cox, S J Blakemore, A H Turaj, R J Oldham, L N Dahal, S Tannheimer, F Forconi, G Packham, M S Cragg
PI3Kδ plays pivotal roles in the maintenance, proliferation, and survival of malignant B-lymphocytes. Although not curative, PI3Kδ inhibitors (PI3Kδi) demonstrate impressive clinical efficacy and, alongside other signaling inhibitors, are revolutionizing the treatment of hematological malignancies. However, only limited in vivo data are available regarding their mechanism of action. With the rising number of novel treatments, the challenge is to identify combinations that deliver curative regimes. A deeper understanding of the molecular mechanism is required to guide these selections...
November 15, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27822137/axitinib-has-antiangiogenic-and-antitumorigenic-activity-in-myxoid-liposarcoma
#14
Lauren T Kerr, Jacqueline F Donoghue, Alexander L Wilding, Terrance G Johns
Myxoid liposarcoma is a rare form of soft-tissue sarcoma. Although most patients initially respond well to treatment, approximately 21% relapse, highlighting the need for alternative treatments. To identify novel treatment regimens and gain a better understanding of myxoid liposarcoma tumor biology, we screened various candidate and approved targeted therapeutics and chemotherapeutics against myxoid liposarcoma cell lines. Therapeutics that target angiogenesis showed antitumor activity. The small molecule inhibitor axitinib, which targets angiogenesis by inhibiting the VEGFR and PDGFR families and c-Kit, inhibited cell cycle progression and induced apoptosis in vitro, as well as having significant antitumor activity against MLS 1765 myxoid liposarcoma xenografts in mice...
2016: Sarcoma
https://www.readbyqxmd.com/read/27819377/downsizing-the-bad-bh3-peptide-to-small-constrained-%C3%AE-helices-with-improved-ligand-efficiency
#15
Nicholas E Shepherd, Rosemary S Harrison, Gloria Ruiz-Gomez, Giovanni Abbenante, Jody M Mason, David P Fairlie
Bcl2 Homology (BH) proteins can either trigger or prevent programmed cell death or apoptosis. Deregulation of the BH protein family network leads to evasion of apoptosis, uncontrolled proliferation and is a hallmark of cancer. Inhibition of pro-survival BH proteins is a promising chemotherapeutic strategy for certain cancers. We have examined whether helix-constrained peptides based on the BAD BH3 domain (residues 103-127) can be downsized to much smaller more drug-like peptides. We report the preparation, structural characterisation, in vitro Bcl-xL inhibition and leukemic T-cell killing ability of 45 linear, mono-, bi- and tricyclic helical peptidomimetics between 8- and 19-residues in length...
November 7, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27816990/combined-antitumor-effect-of-%C3%AE-secretase-inhibitor-and-abt-737-in-notch-expressing-non-small-cell-lung-cancer
#16
Jun Sakakibara-Konishi, Yasuyuki Ikezawa, Satoshi Oizumi, Junko Kikuchi, Eiki Kikuchi, Hidenori Mizugaki, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura
BACKGROUND: Inhibition of Notch by γ-secretase inhibitor (GSI) has been shown to have an antitumor effect in Notch-expressing non-small cell lung cancer (NSCLC) and to induce apoptosis through modulation of Bcl-2 family proteins. In particular, Bim, a BH3-only member of the Bcl-2 family of proteins, has an important role in the induction of apoptosis in NSCLC when cells are treated with GSI. ABT-737, a BH3-only mimetic, targets the pro-survival Bcl-2 family and also induces apoptosis...
November 5, 2016: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/27811212/to-prime-or-not-to-prime-that-is-the-question
#17
Danielle S Potter, Anthony Letai
Mitochondrial priming is regulated by the B-cell lymphoma 2 (BCL-2) family of proteins and determines a cell's "readiness" for apoptosis. A highly primed cell will undergo apoptosis more easily than an unprimed cell in response to apoptotic stimuli via the intrinsic apoptotic pathway. Priming can be measured via BH3 profiling, which uses BH3 peptides derived from the BH3 domain of pro-apoptotic BH3-only BCL-2 family members to provoke a response from viable mitochondria. BH3 profiling can be performed on tumor cells and can identify mechanisms a cell uses to evade apoptosis and anti-apoptotic dependency to the anti-apoptotic BCL-2 family members...
November 3, 2016: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/27806433/targeting-bcl2-with-bh3-mimetics-basic-science-and-clinical-application-of-venetoclax-in-cll-and-related-b-cell-malignancies
#18
Andrew W Roberts, David C S Huang
The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed...
November 2, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27806185/ultraviolet-and-infrared-spectra-of-diboron-in-solid-neon-at-4-k
#19
Jen-Iu Lo, Sheng-Lung Chou, Hsiao-Chi Lu, Yu-Chain Peng, Meng-Yeh Lin, Bing-Ming Cheng, J F Ogilvie
Apart from products H, B, BH, BH2 and BH3 identified from their emission spectra in the UV-visible region, photolysis of diborane(6) dispersed in solid neon at 4 K with far-ultraviolet light from a synchrotron led to observation of absorption line (0,0) of electronic transition A 3Σu- ← X 3Σg- of B2 at 326.39 nm; absorption lines (1,0) of 11B2, 11B10B and 10B2 were recorded at 316.63, 316.40 and 316.15 nm, respectively. △G1/2 of A 3Σu- state for 11B2, 11B10B and 10B2 in solid neon are accordingly derived to be 945, 968 and 993 cm-1, respectively...
November 2, 2016: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
https://www.readbyqxmd.com/read/27806040/cycloheximide-can-induce-bax-bak-dependent-myeloid-cell-death-independently-of-multiple-bh3-only-proteins
#20
Katharine J Goodall, Megan L Finch-Edmondson, Joanne van Vuuren, George C Yeoh, Ian E Gentle, James E Vince, Paul G Ekert, David L Vaux, Bernard A Callus
Apoptosis mediated by Bax or Bak is usually thought to be triggered by BH3-only members of the Bcl-2 protein family. BH3-only proteins can directly bind to and activate Bax or Bak, or indirectly activate them by binding to anti-apoptotic Bcl-2 family members, thereby relieving their inhibition of Bax and Bak. Here we describe a third way of activation of Bax/Bak dependent apoptosis that does not require triggering by multiple BH3-only proteins. In factor dependent myeloid (FDM) cell lines, cycloheximide induced apoptosis by a Bax/Bak dependent mechanism, because Bax-/-Bak-/- lines were profoundly resistant, whereas FDM lines lacking one or more genes for BH3-only proteins remained highly sensitive...
2016: PloS One
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