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https://www.readbyqxmd.com/read/29454280/8-chrysoeriol-as-a-potential-bcl-2-inhibitor-triggers-apoptosis-of-sw1990-pancreatic-cancer-cells
#1
Yiwen Zhang, Zhimei Li, Qiuxia Min, Abulizi Palida, Yiyuan Zhang, Ruotian Tang, Lixia Chen, Hua Li
8-Chrysoeriol, a bioactive flavanoid, was firstly identified to bind directly to BCL-2 as BH3 mimetics by structure-based virtual ligand screening. And 3D docking model revealed the molecular basis of 8-Chrysoeriol targeting to BCL-2. The interaction between 8-Chrysoeriol and BCL-2 was further confirmed using Microscale Thermophoresis (MST) technique. Meanwhile, high expression level of antiapoptotic protein BCL-2 was detected in SW1990 pancreatic cancer cells and 8-Chrysoeriol showed obvious proapoptosis effect against SW1990 in vitro...
February 2, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29441961/clinically-relevant-interactions-of-anti-apoptotic-bcl-2-protein-inhibitors-with-abc-transporters
#2
E Ruzickova, R Janska, P Dolezel, P Mlejnek
In this work we studied clinically relevant interactions between the BH3 mimetics and the ABCB1 and ABCG2 transporters. We observed that the intracellular levels of ABT-263 and ABT-199, but not ABT-737, might be reduced by ABCB1 or ABCG2. Importantly, this effect was proportional to the transporter expression level. High transporter expression levels decreased the intracellular levels of ABT-263 and ABT-199 substantially. Low transporter expression levels, which are clinically relevant, affected the intracellular level of ABT-263 slightly but significantly, however, they failed to decrease the intracellular level of ABT-199 below the control level in parental cells...
December 1, 2017: Die Pharmazie
https://www.readbyqxmd.com/read/29434898/abt-737-and-pictilisib-synergistically-enhance-pitavastatin-induced-apoptosis-in-ovarian-cancer-cells
#3
Elizabeth De Wolf, Christopher De Wolf, Alan Richardson
There is considerable interest in redeploying drugs for use in combination with other oncology therapeutics. The single-agent activity of statins in ovarian cancer has been widely reported, however the drug concentration required to cause cell death is considerably higher than that achieved in patients receiving statin treatment for hypercholesterolemia. Unfortunately, statins can cause myopathy when administered in high doses. One solution to this is to identify drugs that could be used in combination with statins to reduce the dose required and those that may potentially reduce the incidence of adverse side effects...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29408011/bh3-mimetics-as-antifibrotic-therapy-unleashing-the-mitochondrial-pathway-of-apoptosis-in-myofibroblasts
#4
REVIEW
Tobias Kuehl, David Lagares
Organs and tissues in mammals can undergo self-repair following injury. However, chronic or severe tissue injury leads to the development of dense scar tissue or fibrosis at the expense of regeneration. The identification of novel therapeutic strategies aiming at reversing fibrosis is therefore a major clinical unmet need in regenerative medicine. Persistent activation of scar-forming myofibroblasts distinguishes non-resolving pathological fibrosis from self-limited physiological wound healing. Thus, therapeutic strategies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in fibrotic diseases...
January 30, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/29394130/dznep-represses-bcl-2-expression-and-modulates-apoptosis-sensitivity-in-response-to-nutlin-3a
#5
Yalu Zhou, Ricardo E Perez, Lei Duan, Carl G Maki
MDM2 antagonists stabilize and activate wild-type p53, and histone methyltransferase (HMT) inhibitors reduce methylation on histone lysines and arginines. Both MDM2 antagonists and HMT inhibitors are being developed as cancer therapeutics. Wild-type p53 expressing HCT116 colon cancer cells were resistant to apoptosis in response to the MDM2 antagonist Nutlin-3a. However, co-treatment with the HMT inhibitor DZNep sensitized the cells to Nutlin-3a-induced apoptosis. This sensitization resulted from reduced activity of the Bcl-2 gene promoter and a reduction in Bcl-2 mRNA and protein...
February 2, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29381777/the-akt-bcl-2-axis-mediates-survival-of-uterine-leiomyoma-in-a-novel-3d-spheroid-model
#6
Vania Vidimar, Debabrata Chakravarti, Serdar E Bulun, Ping Yin, Romana Nowak, Jian-Jun Wei, J Julie Kim
A deeper understanding of the pathways that drive uterine leiomyoma (ULM) growth and survival requires model systems that more closely mimic the in vivo tumors. This would provide new insights into developing effective therapeutic strategies for these common benign tumors of childbearing-aged women. In this study, we examined the role of BCL-2 in mediating ULM survival in the context of increased AKT and oxidative stress using a novel 3-dimensional (3D), spheroid-based model that more closely resembles the native ULM tumor microenvironment...
January 26, 2018: Endocrinology
https://www.readbyqxmd.com/read/29374168/downregulation-of-mcl-1-and-upregulation-of-puma-using-mtor-inhibitors-enhance-antitumor-efficacy-of-bh3-mimetics-in-triple-negative-breast-cancer
#7
Haolong Li, Lei Liu, Haocai Chang, Zhengzhi Zou, Da Xing
Triple-negative breast cancer (TNBC) shows a higher malignant and poorer clinical outcome compared with other breast cancer subtypes. Albeit that chemotherapy is the first choice for TNBC treatment, rapid emergence of chemoresistance and variability of chemotherapeutic responses in TNBC patients call for novel therapeutic strategies. Here, we reported evidences highlighting that combination of BH3 mimetics and mTOR inhibitors could be a promising therapeutic strategy to improve TNBC treatment. Our results showed that combination of the BH3 mimetic ABT263 and typical mTOR inhibitors, BEZ235 or AZD8055, leads to efficient apoptosis in vitro...
January 26, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29372687/cyclin-dependent-kinase-2-inhibitor-su9516-increases-sensitivity-of-colorectal-carcinoma-cells-caco-2-but-not-ht29-to-bh3-mimetic-abt-737
#8
Andrea Štefaniková, Katarína Klačanová, Ivana Pilchová, Jozef Hatok, Peter Račay
Colorectal carcinoma (CRC) that represents one of the major causes for cancer-related death in humans is often associated with over-expression of anti-apoptotic proteins of Bcl-2 family. The aim of presented study was to determine the effect of ABT-737 inhibitor of anti-apoptotic proteins Bcl-2, Bcl-XL and Bcl-w as well as cyclin-dependent kinase 2 (CDK2) inhibitor SU9516 alone and in combination with ABT-737 on survival of colorectal cell lines HT29 and Caco-2. We have shown that both Caco-2 and HT29 cells that are relatively resistant to ABT-737 are also partially sensitive to SU9516, which increased sensitivity of Caco-2 but not HT29 cells to ABT-737...
December 2017: General Physiology and Biophysics
https://www.readbyqxmd.com/read/29371599/cell-death-based-treatment-of-childhood-cancer
#9
REVIEW
Mike-Andrew Westhoff, Nicolas Marschall, Michael Grunert, Georg Karpel-Massler, Stefan Burdach, Klaus-Michael Debatin
Any therapy that aims at eradicating a cancerous growth will have at its core a cell death-inducing component. Here we argue that paediatric oncology presents with its unique set of considerations and problems, which-while taking the lead from oncological research experiences obtained from the adult population-need to be clinically evaluated independently. This is particularly true when considering long-term side effects. Precision medicine offers a promising new approach in therapy, but given as a monotherapy and in a limited combination, as found in an apoptosis inducer/sensitiser combination, it will most likely lead to mutation escape of the target cell population and the emergence of resistance...
January 25, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29348439/dual-suppression-of-inner-and-outer-mitochondrial-membrane-functions-augments-apoptotic-responses-to-oncogenic-mapk-inhibition
#10
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/29340082/reciprocal-sensitivity-of-diffuse-large-b-cell-lymphoma-cells-to-bcl-2-inhibitors-bird-2-versus-venetoclax
#11
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/29335437/deubiquitinase-usp13-dictates-mcl1-stability-and-sensitivity-to-bh3-mimetic-inhibitors
#12
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/29312548/mimicking-the-bim-bh3-domain-overcomes-resistance-to-egfr-tyrosine-kinase-inhibitors-in-egfr-mutant-non-small-cell-lung-cancer
#13
Jinjing Xia, Hao Bai, Bo Yan, Rong Li, Minhua Shao, Liwen Xiong, Baohui Han
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied to treat EGFR-mutant non-small cell lung cancer (NSCLC). BIM is a BH3 domain-containing protein encoded by BCL2L11. Some EGFR-mutant NSCLC patients showing BIM deletion polymorphism are resistant to EGFR TKIs. We retrospectively investigated BIM deletion polymorphism in NSCLC patients, its correlation with EGFR TKI (erlotinib) resistance, and the mechanism underlying the drug resistance. Among 245 EGFR-mutant NSCLC patients examined, BIM deletion polymorphism was detected in 43 (12...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29287939/phosphoinositide-dependent-protein-kinase-1-is-a-potential-novel-therapeutic-target-in-mantle-cell-lymphoma
#14
Saori Maegawa, Yoshiaki Chinen, Yuji Shimura, Kazuna Tanba, Tomoko Takimoto, Yoshimi Mizuno, Yayoi Matsumura-Kimoto, Saeko Kuwahara-Ota, Taku Tsukamoto, Tsutomu Kobayashi, Shigeo Horiike, Masafumi Taniwaki, Junya Kuroda
Mantle cell lymphoma (MCL) is a relatively rare subtype of B-cell non-Hodgkin lymphoma (NHL) that has a poor prognosis, despite recent advances in immunochemotherapy and molecular targeted therapeutics against NHL. Therefore, development of a new therapeutic strategy for MCL is urgently needed. In this study, we first show that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), an oncogenic serine-threonine protein kinase, is commonly expressed in its phosphorylated activate form in patient-derived tumor cells of various types of B-cell NHL cells, including diffuse large B cell lymphoma, follicular lymphoma and MCL...
December 26, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29247826/cytostatic-hydroxycoumarin-ot52-induces-er-golgi-stress-and-stat3-inhibition-triggering-non-canonical-cell-death-and-synergy-with-bh3-mimetics-in-lung-cancer
#15
Jin-Young Lee, Oualid Talhi, Dongman Jang, Claudia Cerella, Anthoula Gaigneaux, Kyu-Won Kim, Jung Weon Lee, Mario Dicato, Khaldoun Bachari, Byung Woo Han, Artur M S Silva, Barbora Orlikova, Marc Diederich
Coumarins are natural compounds with antioxidant, anti-inflammatory and anti-cancer potential known to modulate inflammatory pathways. Here, non-toxic biscoumarin OT52 strongly inhibited proliferation of non-small cell lung cancer cells with KRAS mutations, inhibited stem-like characteristics by reducing aldehyde dehydrogenase expression and abrogated spheroid formation capacity. This cytostatic effect was characterized by cell cycle arrest and onset of senescence concomitant with endoplasmic reticulum and Golgi stress, leading to metabolic alterations...
December 13, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29241222/flavopiridol-enhances-abt-199-sensitivity-in-unfavourable-risk-multiple-myeloma-cells-in-vitro-and-in-vivo
#16
Liang Zhou, Yu Zhang, Deepak Sampath, Joel Leverson, Yun Dai, Maciej Kmieciak, Matthew Nguyen, Robert Z Orlowski, Steven Grant
BACKGROUND: The BCL-2-specific BH3-mimetic ABT-199 (venetoclax) has been reported to be principally active against favourable-risk multiple myeloma (MM) cells, prompting efforts to extend its activity to include more resistant, higher-risk MM subsets. METHODS: Effects of the CDK9 inhibitor flavopiridol (FP; alvocidib) on responses to ABT-199 were examined in MM cells. Cell death and protein expression were evaluated by western blot and immunofluorescence. Xenograft models were used to study combination effects in vivo...
December 14, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29237758/targeted-apoptosis-of-myofibroblasts-with-the-bh3-mimetic-abt-263-reverses-established-fibrosis
#17
David Lagares, Alba Santos, Paula E Grasberger, Fei Liu, Clemens K Probst, Rod A Rahimi, Norihiko Sakai, Tobias Kuehl, Jeremy Ryan, Patrick Bhola, Joan Montero, Mohit Kapoor, Murray Baron, Xaralabos Varelas, Daniel J Tschumperlin, Anthony Letai, Andrew M Tager
Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in diseases such as scleroderma, a heterogeneous autoimmune disease characterized by multiorgan fibrosis. We demonstrate that fibroblast-to-myofibroblast differentiation driven by matrix stiffness increases the mitochondrial priming (proximity to the apoptotic threshold) of these activated cells...
December 13, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29229994/autophagy-induced-during-apoptosis-degrades-mitochondria-and-inhibits-type-i-interferon-secretion
#18
Lisa M Lindqvist, Daniel Frank, Kate McArthur, Toby A Dite, Michael Lazarou, Jonathan S Oakhill, Benjamin T Kile, David L Vaux
Cells undergoing Bax/Bak-mediated apoptosis exhibit signs of autophagy, but how it is activated and its significance is unknown. By directly activating Bax/Bak with BH3-only proteins or BH3 mimetic compounds, we demonstrate that mitochondrial damage correlated with a rapid increase in intracellular [AMP]/[ATP], phosphorylation of 5' AMP-activated protein kinase (AMPK), and activation of unc-51 like autophagy activating kinase 1 (ULK1). Consequently, autophagic flux was triggered early in the apoptotic pathway, as activation of the apoptosome and caspases were not necessary for its induction...
December 11, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29188305/synergistic-cytotoxicity-of-a-prostate-cancer-specific-immunotoxin-in-combination-with-the-bh3-mimetic-abt-737
#19
Theresa Noll, Susanne Schultze-Seemann, Irina Kuckuck, Marta Michalska, Philipp Wolf
In many tumors, including prostate cancer, anti-apoptotic members of the Bcl-2 family are overexpressed and cause cell death resistance, which is a typical hallmark of cancer. Different therapeutic approaches, therefore, aim to restore the death mechanisms for enhanced apoptosis. Our recombinant immunotoxin D7(VL-VH)-PE40 is composed of the scFv D7(VL-VH) against the prostate-specific membrane antigen (PSMA) on the surface of prostate cancer cells and of the cytotoxic domain of the bacterial toxin Pseudomonas Exotoxin A (PE40)...
November 29, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29166790/towards-re-purposing-bh3-mimetics-in-legionella-and-viral-infections
#20
Thomas Naderer
No abstract text is available yet for this article.
November 22, 2017: Expert Review of Anti-infective Therapy
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