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https://www.readbyqxmd.com/read/28525842/indole-coumarin-thiadiazole-hybrids-an-appraisal-of-their-mcf-7%C3%A2-cell-growth-inhibition-apoptotic-antimetastatic-and-computational-bcl-2-binding-potential
#1
Pooja R Kamath, Dhanya Sunil, Manu M Joseph, Abdul Ajees Abdul Salam, Sreelekha T T
Cancer therapeutic potential of thiadiazole hybrids incorporating pharmacologically active indole and coumarin moieties have not been explored much. In the current investigation, three new thiadiazole hybrids with spacers of varying lengths linking indole and thiadiazole units were synthesized and their structures were well-established using various spectroscopic techniques. 3-(1-(5-(3-(1H-indol-3-yl)propyl)-1,3,4-thiadiazol-2-ylimino)ethyl)-6-bromo-2H-chromen-2-one (IPTBC) exhibited dose-dependent cytotoxicity in breast adenocarcinoma (MCF-7) cells...
May 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28522750/inhibition-of-mitochondrial-matrix-chaperones-and-anti-apoptotic-bcl-2-family-proteins-empower-antitumor-therapeutic-responses
#2
Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Rolando Perez-Lorenzo, Basil Horst, Matei Banu, Kevin A Roth, Jeffrey N Bruce, Peter Canoll, Dario C Altieri, Markus D Siegelin
Rational therapeutic approaches based on synthetic lethality may improve cancer management. Based on a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and Obatoclax) or selective (ABT199, WEHI-539 and A1210477), along with the established mitochondrial matrix chaperone inhibitor Gamitrinib-TPP...
May 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28511583/deciphering-the-crucial-residues-involved-in-heterodimerization-of-bak-peptide-and-anti-apoptotic-proteins-for-apoptosis
#3
Parthiban Marimuthu, Kalaimathy Singaravelu
B-cell lymphoma 2 (Bcl-2) family proteins are the central regulators of apoptosis, function via mitochondrial outer membrane permeabilization. The family members are involved in several stages of apoptosis regulation. The overexpression of the anti-apoptotic proteins leads to several cancer pathological conditions. This overexpression is modulated or inhibited by heterodimerization of pro-apoptotic BH3 domain or BH3-only peptides to the hydrophobic groove present at the surface of anti-apoptotic proteins. Additionally, the heterodimerization displayed differences in binding affinity profile among the pro-apoptotic peptides binding to anti-apoptotic proteins...
May 16, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28489572/ck2-and-pi3k-are-direct-molecular-targets-of-quercetin-in-chronic-lymphocytic-leukaemia
#4
Maria Russo, Alfonsina Milito, Carmela Spagnuolo, Virginia Carbone, Anders Rosén, Paola Minasi, Fabio Lauria, Gian Luigi Russo
Despite the encouraging results of the innovative therapeutic treatments, complete remission is uncommon in patients affected by chronic lymphocytic leukaemia, which remains an essentially incurable disease. Recently, clinical trials based on BH3-mimetic drugs showed positive outcomes in subjects with poor prognostic features. However, resistance to treatments occurs in a significant number of patients. We previously reported that the multi-kinase inhibitor quercetin, a natural flavonol, restores sensitivity to ABT-737, a BH3-mimetic compound, in both leukemic cell lines and B-cells isolated from patients...
April 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28489092/reactivity-studies-of-silylene-phc-ntbu-2-c5me5-si-reactions-with-m-cod-cl-2-m-rh-i-ir-i-s-se-te-and-bh3
#5
Sebastian Kaufmann, Sebastian Schäfer, Michael T Gamer, Peter W Roesky
The reactivity of recently introduced N-heterocyclic silylene [PhC(NtBu)2](C5Me5)Si was evaluated. Three different reaction pathways were studied: (1) coordination to a Lewis acid, (2) oxidation by chalcogenides, and (3) coordination to transition metal complexes. The reaction of the silylene with BH3 led to the adduct [PhC(NtBu)2](C5Me5)Si(BH)3. Oxidation with the elemental chalcogens sulphur, selenium, and tellurium resulted in the corresponding silicon(iv)-chalcogenide compounds [PhC(NtBu)2](C5Me5)SiS, [PhC(NtBu)2](C5Me5)SiSe and [PhC(NtBu)2](C5Me5)SiTe...
May 10, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28486749/catalytic-electrophilic-c-h-borylation-using-nhc%C3%A2-boranes-and-iodine-forms-c2-not-c3-borylated-indoles
#6
Michael Ingleson, John McGough, Jessica Cid
Activation of N-heterocyclic carbene boranes (NHC·BH3) by I2 enables the metal free catalytic C-H borylation of heteroarenes with formation of H2 as the by-product in a process that uses only bench stable precursors. The borylation of indoles using NHCBH3/I2 produces C2-borylated indoles exclusively in contrast to other catalytic electrophilic C-H borylation methods. Mechanistic studies indicate that this is due to C3 to C2 boron migration facilitated by the absence of exogenous Brønsted bases. Thus this C-H borylation methodology proceeds under sufficiently Brønsted acidic conditions to enable the thermodynamic C2-borylated indole isomer to be formed instead of the C3 borylated-isomer...
May 9, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28469964/comprehensive-pharmacological-profiling-of-neurofibromatosis-cell-lines
#7
Jianman Guo, Michael R Grovola, Hong Xie, Grace E Coggins, Patrick Duggan, Rukhsana Hasan, Jiale Huang, Danny W Lin, Claire Song, Gabriela M Witek, Simon Berritt, David C Schultz, Jeffrey Field
Patients with Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are predisposed to tumors of the nervous system. NF1 patients predominantly develop neurofibromas, and Malignant Peripheral Nerve Sheath Tumors (MPNST) while NF2 patients develop schwannomas and meningiomas. Here we quantified the drug sensitivities of NF1 and NF2 tumor cell lines in a high throughput platform. The platform contained a comprehensive collection of inhibitors of MEK, RAF, RAS, farnesyl transferase, PAK and ERK, representative drugs against many other cancer pathways including Wnt, Hedgehog, p53, EGF, HDAC, as well as classical cytotoxic agents recommended for treating MPNST, such as doxorubicin and etoposide...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28468776/vulnerability-of-small-cell-lung-cancer-to-apoptosis-induced-by-the-combination-of-bet-bromodomain-proteins-and-bcl2-inhibitors
#8
Lloyd T Lam, Xiaoyu Lin, Emily J Faivre, Ziping Yang, Xiaoli Huang, Denise M Wilcox, Richard J Bellin, Sha Jin, Stephen K Tahir, Michael Mitten, Terry Magoc, Anahita Bhathena, Warren M Kati, Daniel H Albert, Yu Shen, Tamar Uziel
10% to 15% of all lung cancers are small cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis such as MYC, CCND2, and BCL2L1 Here, we demonstrate that ~50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075...
May 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28455241/in%C3%A2-vitro-and-in%C3%A2-vivo-anti-uveal-melanoma-activity-of-jsl-1-a-novel-hdac-inhibitor
#9
Yun Wang, Maoxing Liu, Yanli Jin, Sheng Jiang, Jingxuan Pan
Uveal melanoma (UM) is the most common intraocular malignant neoplasm in adults. Despite the availability of enucleation, radiation and chemotherapy, the prognosis of patients with metastasis remains poor. Therefore, novel effective therapies for patients with metastatic UM are urgently needed. In the present study, we demonstrated that JSL-1, a novel HDAC inhibitor, effectively inhibited the proliferation. JSL-1 induced apoptosis with increased expression of proapoptotic BH3-only protein BIM in UM cells. JSL-1 suppressed migration and invasion of UM cells with MMP-2 decreased...
April 26, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28454468/ethanolic-extract-of-thevetia-peruviana-flowers-enhances-tnf-%C3%AE-and-trail-induced-apoptosis-of-human-cervical-cancer-cells-via-intrinsic-and-extrinsic-pathways
#10
Chittima Managit, Hiroaki Sakurai, Ikuo Saiki
Tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) are promising candidates for cancer treatment due to their ability to induce apoptosis through death receptor stimulation. However, their usage may be limited due to the resistance of cancer cells to TNF-α- and TRAIL-induced apoptosis. Currently, there is interest in screening for natural products that can sensitize cancer cells to TNF-α- and TRAIL-induced apoptosis for their use in combination with TNF-α or TRAIL. It was previously reported that the bark extract of Thevetia peruviana showed a reversal effect on TRAIL-resistance in human gastric adenocarcinoma cell lines...
April 2017: Oncology Letters
https://www.readbyqxmd.com/read/28449207/targeting-anti-apoptotic-bcl2-family-proteins-in-haematological-malignancies-from-pathogenesis-to-treatment
#11
REVIEW
Meike Vogler, Harriet S Walter, Martin J S Dyer
The B-cell lymphoma 2 (BCL2) family of proteins comprise key regulators of apoptosis and are implicated in the pathogenesis of many malignancies, including lymphomas and leukaemias. Targeting of BCL2 proteins can be directly toxic to tumour cells or render them more sensitive to chemotherapy. Inhibition of the anti-apoptotic functions of BCL2 proteins using structure-based design to produce specific inhibitors of protein-protein interactions has been achieved for BCL2, MCL1 and BCL-XL (also termed BCL2L1), providing an armamentarium of new targeted therapies called BH3-mimetics...
April 27, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28448129/alkaline-earth-derivatives-of-the-reactive-hb-c6f5-3-anion
#12
Mathew D Anker, Merle Arrowsmith, Rory L Arrowsmith, Michael S Hill, Mary F Mahon
The β-diketiminato magnesium amidoboranes [HC{(Me)CNDipp}2Mg(NMe2BH2NMe2·BH3)] and [HC{(t-Bu)CNDipp}2Mg(NMe2·BH3)] are readily converted to the corresponding derivatives of the [HB(C6F5)3](-) anion by treatment with B(C6F5)3. The bis(borohydride) derivatives of the heaviest alkaline-earth elements, strontium and barium, may be similarly synthesized by reaction of strontium or barium dimethylamidoboranes and B(C6F5)3 and by metathesis reactions of either SrI2 or BaI2 and 2 molar equiv of K(HB(C6F5)3). The strontium and barium compounds have been fully characterized in solution and in the solid state as the respective tris(diethyl ether) and tetrakis(tetrahydrofuran) adducts...
April 27, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28447717/knockdown-of-zfpl1-results-in-increased-autophagy-and-autophagy%C3%A2-related-cell-death-in-nci%C3%A2-n87-and-bgc%C3%A2-823-human-gastric-carcinoma-cell-lines
#13
Yong-Zheng Xie, Wan-Li Ma, Ji-Ming Meng, Xue-Qun Ren
Macroautophagy, which will hereafter be referred to as autophagy, is an evolutionarily conserved process, during which cells recycle and remove damaged organelles and proteins in response to cellular stress. However, the mechanisms underlying the regulation of autophagy remain to be fully elucidated. The present study demonstrated that knockdown of zinc finger protein like 1 (ZFPL1) induces autophagy and increases autophagic cell death in NCI‑N87 and BGC‑823 human gastric carcinoma cell lines. To examine the role of ZFPL1 in gastric carcinoma cells, ZFPL1 expression was downregulated by lentiviral infection...
May 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28446054/pharmacotherapy-of-relapsed-refractory-chronic-lymphocytic-leukemia
#14
Abdallah Abou Zahr, Prithviraj Bose, Michael J Keating
The treatment of relapsed/refractory (RR) CLL has been revolutionized by the advent of the new oral inhibitors of B-cell receptor (BCR) signaling and the pro-survival protein, B-cell lymphoma 2 (BCL2). Additionally, new and more potent monoclonal antibodies against CD20 have replaced/may replace rituximab in many settings. Areas covered: Herein, we review the entire therapeutic landscape of RR CLL, with particular attention to the new small-molecule kinase inhibitors and BH3-mimetics. We discuss preclinical data with these agents in CLL, cover available efficacy and safety information, and examine potential resistance mechanisms and possible rational combinations to circumvent them...
May 16, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28445931/high-glucose-induces-apoptosis-via-upregulation-of-bim-expression-in-proximal-tubule-epithelial-cells
#15
Xiao-Qian Zhang, Jian-Jun Dong, Tian Cai, Xue Shen, Xiao-Jun Zhou, Lin Liao
Diabetic nephropathy is the primary cause of end-stage renal disease. Apoptosis of tubule epithelial cells is a major feature of diabetic nephropathy. The mechanisms of high glucose (HG) induced apoptosis are not fully understood. Here we demonstrated that, HG induced apoptosis via upregulating the expression of proapoptotic Bcl-2 homology domain 3 (BH3)-only protein Bim protein, but not bring a significant change in the baseline level of autophagy in HK2 cells. The increase of Bim expression was caused by the ugregulation of transcription factors, FOXO1 and FOXO3a...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28443864/planar-chiral-ferrocenylphosphine-borane-complexes-featuring-agostic-type-b-he-e-hg-sn-interactions
#16
Alain C Tagne Kuate, Roger A Lalancette, F Jäkle
The synthesis of ferrocenylphosphine-borane adducts 1,2-fc(E)(PPh2·BH3) (E = SnR2R', HgX; 1,2-fc = 1,2-ferrocenediyl) that are substituted with organotin or organomercury Lewis acid moieties in ortho-position is presented. Several compounds that feature two ferrocenylphosphine-borane moieties bridged by Sn or Hg are also introduced. The products are fully characterized by multinuclear NMR spectroscopy, high-resolution MALDI-TOF mass spectrometry and elemental analysis. The attachment of the Lewis acid substituent to the same Cp ring of the ferrocene results in planar-chirality and the close proximity between the boron hydride group and the Lewis acid is expected to allow for agostic-type B-HE (E = Sn, Hg) interactions...
May 16, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28439883/an-update-for-richter-syndrome-new-directions-and-developments
#17
REVIEW
Toby A Eyre, Anna Schuh
High-grade transformation of chronic lymphocytic leukaemia [Richter syndrome (RS)] is rare and represents a unique and uncommon clinical challenge. Clonally related diffuse large B cell type RS is a chemotherapy-resistant and devastating disease. Patients are typically elderly, immunosuppressed and present with a rapidly deteriorating performance status. Historical outcomes suggest a median overall survival of approximately 8 months. RS remains is an area of high unmet clinical need. The molecular profile and treatment needs of patients are likely to change over time with the advent of novel B cell receptor inhibitors, monoclonal antibodies and BH3 mimetics...
April 25, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28436637/-research-progress-on-mechanism-of-nix-mediated-mitophagy
#18
Yanrong Zheng, Xiangnan Zhang, Zhong Chen
Autophagy is fundamental to maintain cellular homeostasis. As one kind of the most well-studied selective autophagy, autophagy of mitochondria (mitophagy)is crucial for the clearance of damaged mitochondria. Mitophagy dysfunction has been proved to be closely associated with many human diseases. Nix is a key protein for mitophagy during the maturation of reticulocytes. However, the detailed molecular mechanisms underlying Nix-mediated mitophagy are not fully understood. This article summarizes three possible working models of Nix in mitophagy induction...
January 25, 2017: Zhejiang da Xue Xue Bao. Yi Xue Ban, Journal of Zhejiang University. Medical Sciences
https://www.readbyqxmd.com/read/28425914/epstein-barr-virus-ensures-b-cell-survival-by-uniquely-modulating-apoptosis-at-early-and-late-times-after-infection
#19
Alexander M Price, Joanne Dai, Quentin Bazot, Luv Patel, Pavel A Nikitin, Reza Djavadian, Peter S Winter, Cristina A Salinas, Ashley Perkins Barry, Kris C Wood, Eric C Johannsen, Anthony Letai, Martin J Allday, Micah A Luftig
Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers. EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFκB and is critical for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the mechanism of survival in the absence of LMP1/NFκB early after infection...
April 20, 2017: ELife
https://www.readbyqxmd.com/read/28425584/changes-in-ciap2-survivin-and-bimel-expression-characterize-the-switch-from-autophagy-to-apoptosis-in-prolonged-starvation
#20
A Hay-Koren, S Bialik, V Levin-Salomon, A Kimchi
BACKGROUND: Autophagy is a catabolic process involving the engulfment of cytoplasmic content within autophagosomes followed by their delivery to lysosomes. This process is a survival mechanism, enabling cells to cope with nutrient deprivation by degradation and recycling of macromolecules. Yet during continued stress such as prolonged starvation, a switch from autophagy to apoptosis is often detected. OBJECTIVE: In this work, we characterized the temporal dynamics of the transition from autophagy towards apoptosis with the aim of elucidating the molecular mechanism regulating the switch from survival autophagy to apoptotic cell death...
May 2017: Journal of Internal Medicine
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