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BH3 mimetics

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https://www.readbyqxmd.com/read/29885833/combination-therapy-with-bh3-mimetic-and-hyperthermia-tends-to-be-more-effective-on-anti-melanoma-treatment
#1
Zhen Shi, Bin Lan, Baowei Peng, Xuefeng Wang, Ganggang Zhang, Xiaohu Li, Fang Guo
Malignant melanoma has shown increased incidence and high mortality rate in the last three decades. In this study, we investigated whether combination therapy with ch282-5 (a novel BH3 mimetic) and microwave hyperthermia could display synergistic antitumor effects against melanoma. Our results indicated that combination therapy reduced the viability and proliferation of melanoma cells. Through inhibiting the expression of anti-apoptotic proteins of Bcl-2 and IAP family and activating MAPK proteins, combined hyperthermia enhanced ch282-5-induced apoptosis...
June 7, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29858681/effects-of-sequentially-applied-single-and-combined-temozolomide-hydroxychloroquine-and-at101-treatment-in-a-long-term-stimulation-glioblastoma-in-vitro-model
#2
Vivian Adamski, Christina Schmitt, Florian Ceynowa, Rainer Adelung, Ralph Lucius, Michael Synowitz, Kirsten Hattermann, Janka Held-Feindt
PURPOSE: Glioblastoma multiforme (GBM) is a poorly curable disease due to its heterogeneity that enables single cells to survive treatment regimen and initiate tumor regrowth. Although some progress in therapy has been achieved in the last years, the efficient treatment of GBMs is still a clinical challenge. Besides the standard therapeutic drug temozolomide (TMZ), quinoline-based antimalarial drugs such as hydroxychloroquine (HCQ) and BH3 mimetics such as AT101 were considered as possible drugs for GBM therapy...
June 1, 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29858601/bcl-2-selective-inhibitor-abt-199-primes-rhabdomyosarcoma-cells-to-histone-deacetylase-inhibitor-induced-apoptosis
#3
Ulrike Heinicke, Tinka Haydn, Sarah Kehr, Meike Vogler, Simone Fulda
BH3 mimetics are emerging novel anticancer therapeutics that potently and specifically inhibit antiapoptotic BCL-2 proteins and thereby induce cell death in many cancer entities. Previously, we demonstrated that JNJ-26481585 (JNJ), a second-generation histone deacetylase inhibitor (HDACI), engages mitochondrial apoptosis via upregulation of several BH3-only proteins. In the present study, we describe synergistic interactions of JNJ with BH3 mimetics (i.e. ABT-737, ABT-199) in rhabdomyosarcoma (RMS) cells. Importantly, JNJ synergizes with ABT-199 to trigger apoptosis in primary-derived RMS cells isolated from tumor samples, underlining the translational importance of combining these compounds and their potential to improve cancer therapy...
June 1, 2018: Oncogene
https://www.readbyqxmd.com/read/29792865/aspirin-restores-abt-737-mediated-apoptosis-in-human-renal-carcinoma-cells
#4
Yen-Chuan Ou, Jian-Ri Li, Jiaan-Der Wang, Wen-Ying Chen, Yu-Hsiang Kuan, Ching-Ping Yang, Su-Lan Liao, Hsi-Chi Lu, Chun-Jung Chen
Aspirin is a novel chemopreventive agent against malignancy. However, outcomes of aspirin monotherapy of renal cell carcinoma (RCC) are inconsistent across studies. ABT-737, an BH3 mimetic inhibitor, is also a promising antitumor drug. Cancer cells including those from RCC, that have high levels of Mcl-1, are refractory to ABT-737-induced apoptosis. We here investigated how aspirin treatment modulates the ABT-737-induced apoptosis. Using the in vitro model of human 786-O cells, we showed that aspirin had sensitized cells to ABT-737 induced apoptosis...
May 21, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29767411/mek1-2-inhibition-by-binimetinib-is-effective-as-a-single-agent-and-potentiates-the-actions-of-venetoclax-and-abt-737-under-conditions-that-mimic-the-chronic-lymphocytic-leukaemia-cll-tumour-microenvironment
#5
Kyle Crassini, Yandong Shen, William S Stevenson, Richard Christopherson, Chris Ward, Stephen P Mulligan, O Giles Best
The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma-conditioned media and phorbol myristylate (PMA)...
May 16, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29759975/restoring-the-switch-for-cancer-cell-death-targeting-the-apoptosis-signaling-pathway
#6
REVIEW
Clement Chung
PURPOSE: The relevance of apoptosis to cancer development and pharmacologic agents that target this pathway in selected malignancies are described. SUMMARY: Apoptosis is a tightly regulated biological process mediated by both proapoptotic (i.e., prodeath) and antiapoptotic (i.e., prosurvival) proteins. While apoptosis represents a well-established effector mechanism induced by conventional chemotherapy in many malignancies, the development of apoptosis-based targeted therapy is relatively new...
May 14, 2018: American Journal of Health-system Pharmacy: AJHP
https://www.readbyqxmd.com/read/29753379/the-antiarrhythmic-drug-amiodarone-decreases-akt-activity-and-sensitizes-human-acute-myeloid-leukemia-cells-to-apoptosis-by-abt-263
#7
Corey J Ketchem, Cory Kucera, Aditya Barve, Levi J Beverly
BACKGROUND: Successful treatment of leukemia requires new medications to combat drug resistance, but the development of novel therapies is an arduous and risky endeavor. Repurposing currently approved drugs or those already in clinical development to treat other indications is a more practical approach. Moreover, combinatorial therapeutics are often more efficacious than single agent therapeutics because the former can simultaneously target multiple pathways that mitigate tumor aggressiveness and induce cancer cell death...
May 2018: American Journal of the Medical Sciences
https://www.readbyqxmd.com/read/29747654/bcl-2-as-therapeutic-target-for-hematological-malignancies
#8
REVIEW
Guilherme Fleury Perini, Glaciano Nogueira Ribeiro, Jorge Vaz Pinto Neto, Laura Tojeiro Campos, Nelson Hamerschlak
Disruption of the physiologic balance between cell proliferation and cell death is an important step of cancer development. Increased resistance to apoptosis is a key oncogenic mechanism in several hematological malignancies and, in many cases, especially in lymphoid neoplasias, has been attributed to the upregulation of BCL-2. The BCL-2 protein is the founding member of the BCL-2 family of apoptosis regulators and was the first apoptosis modulator to be associated with cancer. The recognition of the important role played by BCL-2 for cancer development and resistance to treatment made it a relevant target for therapy for many diseases, including solid tumors and hematological neoplasias...
May 11, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29743589/dual-inhibition-of-bcl-xl-and-mcl-1-is-required-to-induce-tumour-regression-in-lung-squamous-cell-carcinomas-sensitive-to-fgfr-inhibition
#9
Clare E Weeden, Casey Ah-Cann, Aliaksei Z Holik, Julie Pasquet, Jean-Marc Garnier, Delphine Merino, Guillaume Lessene, Marie-Liesse Asselin-Labat
Genetic alterations in the fibroblast growth factor receptors (FGFRs) have been described in multiple solid tumours including bladder cancer, head and neck and lung squamous cell carcinoma (SqCC). However, recent clinical trials showed limited efficacy of FGFR-targeted therapy in lung SqCC, suggesting combination therapy may be necessary to improve patient outcomes. Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We therefore hypothesised that combining BH3-mimetics, potent inhibitors of pro-survival proteins, with FGFR-targeted therapy may enhance the killing of SqCC cells...
May 10, 2018: Oncogene
https://www.readbyqxmd.com/read/29743557/inhibition-of-bcl-2-bcl-xl-and-c-met-causes-synthetic-lethality-in-model-systems-of-glioblastoma
#10
Yiru Zhang, Chiaki Tsuge Ishida, Chang Shu, Giulio Kleiner, Maria J Sanchez-Quintero, Elena Bianchetti, Catarina M Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin
Recent data suggest that glioblastomas (GBM) activate the c-MET signaling pathway and display increased levels in anti-apoptotic Bcl-2 family members. Therefore, targeting these two deregulated pathways for therapy might yield synergistic treatment responses. We applied extracellular flux analysis to assess tumor metabolism. We found that combined treatment with ABT263 and Crizotinib synergistically reduces the proliferation of glioblastoma cells, which was dependent on dual inhibition of Bcl-2 and Bcl-xL. The combination treatment led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases...
May 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29732004/s55746-is-a-novel-orally-active-bcl-2-selective-and-potent-inhibitor-that-impairs-hematological-tumor-growth
#11
Patrick Casara, James Davidson, Audrey Claperon, Gaëtane Le Toumelin-Braizat, Meike Vogler, Alain Bruno, Maïa Chanrion, Gaëlle Lysiak-Auvity, Thierry Le Diguarher, Jérôme-Benoît Starck, Ijen Chen, Neil Whitehead, Christopher Graham, Natalia Matassova, Pawel Dokurno, Christopher Pedder, Youzhen Wang, Shumei Qiu, Anne-Marie Girard, Emilie Schneider, Fabienne Gravé, Aurélie Studeny, Ghislaine Guasconi, Francesca Rocchetti, Sophie Maïga, Jean-Michel Henlin, Frédéric Colland, Laurence Kraus-Berthier, Steven Le Gouill, Martin J S Dyer, Roderick Hubbard, Mike Wood, Martine Amiot, Gerald M Cohen, John A Hickman, Erick Morris, James Murray, Olivier Geneste
Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29682179/antiapoptotic-bcl-2-proteins-determine-sorafenib-regorafenib-resistance-and-bh3-mimetic-efficacy-in-hepatocellular-carcinoma
#12
Anna Tutusaus, Milica Stefanovic, Loreto Boix, Blanca Cucarull, Aynara Zamora, Laura Blasco, Pablo García de Frutos, Maria Reig, Jose C Fernandez-Checa, Montserrat Marí, Anna Colell, Jordi Bruix, Albert Morales
Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29581547/protein-targeting-chimeric-molecules-specific-for-bromodomain-and-extra-terminal-motif-family-proteins-are-active-against-pre-clinical-models-of-multiple-myeloma
#13
Xiaohui Zhang, Hans C Lee, Fazal Shirazi, Veerabhadran Baladandayuthapani, Heather Lin, Isere Kuiatse, Hua Wang, Richard J Jones, Zuzana Berkova, Ram Kumar Singh, Jing Lu, Yimin Qian, Kanak Raina, Kevin G Coleman, Craig M Crews, Bingzong Li, Huihan Wang, Yared Hailemichael, Sheeba K Thomas, Zhiqiang Wang, R Eric Davis, Robert Z Orlowski
Bromodomain and extraterminal (BET) domain containing protein (BRD)-4 modulates the expression of oncogenes such as c-myc, and is a promising therapeutic target in diverse cancer types. We performed pre-clinical studies in myeloma models with bi-functional protein-targeting chimeric molecules (PROTACs) which target BRD4 and other BET family members for ubiquitination and proteasomal degradation. PROTACs potently reduced the viability of myeloma cell lines in a time-dependent and concentration-dependent manner associated with G0 /G1 arrest, reduced levels of CDKs 4 and 6, increased p21 levels, and induction of apoptosis...
March 27, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29580266/synergistic-anti-proliferative-effects-of-combination-of-abt-263-and-mcl-1-selective-inhibitor-a-1210477-on-cervical-cancer-cell-lines
#14
Benedict Shi Xiang Lian, Angeline En Hui Yek, Hemalata Shuvas, Siti Fairus Abdul Rahman, Kalaivani Muniandy, Nethia Mohana-Kumaran
OBJECTIVE: There are number of studies which report that BCL-2 anti-apoptotic proteins (e.g. BCL-2, BCL-XL, and MCL-1) are highly expressed in cervical cancer tissues compared to the normal cervical epithelia. Despite these reports, targeting these proteins for cervical cancer treatment has not been explored extensively. BH3-mimetics that inhibit specific BCL-2 anti-apoptotic proteins may hold encouraging treatment outcomes for cervical cancer management. Hence, the aim of this pilot study is to investigate the sensitivity of cervical cancer cell lines to combination of two BH3-mimetics namely ABT-263 which selectively inhibits BCL-2, BCL-XL and BCL-w and A-1210477, a selective MCL-1 inhibitor...
March 27, 2018: BMC Research Notes
https://www.readbyqxmd.com/read/29543705/glycycoumarin-sensitizes-liver-cancer-cells-to-abt-737-by-targeting-de-novo-lipogenesis-and-topk-survivin-axis
#15
Enxiang Zhang, Shutao Yin, Xiaotong Lu, Linhu Ye, Lihong Fan, Hongbo Hu
Glycycoumarin (GCM) is a representative of bioactive coumarin compounds isolated from licorice, an edible and medicinal plant widely used for treating various diseases including liver diseases. The purpose of the present study is to examine the possibility of GCM as a sensitizer to improve the efficacy of BH3 mimetic ABT-737 against liver cancer. Three liver cancer cell lines (HepG2, Huh-7 and SMMC-7721) were used to evaluate the in vitro combinatory effect of ABT-737/GCM. HepG2 xenograft model was employed to assess the in vivo efficacy of ABT-737/GCM combination...
March 15, 2018: Nutrients
https://www.readbyqxmd.com/read/29529398/design-and-screening-of-syringic-acid-analogues-as-bax-activators-an-in-silico-approach-to-discover-bh3-mimetics
#16
Srinivasulu Cheemanapalli, Anuradha C M, Suresh Babu Pakala, Suresh Kumar Chitta
Although BAX, which is a molecular hit squad that incentive apoptosis was found to be an attractive emerging target for anticancer agents. The molecular mechanism of small molecules/peptides involved in the BAX activation was remain unknown. The present focus of the study is to identification and development of novel molecules which are precisely activates BAX mediated apoptosis. In this process we identified some syringic acid analogues associated with the BAX hydrophobic groove by a virtual-screen approach...
March 9, 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29520705/targeting-bcl-2-in-hematologic-malignancies
#17
Nadia Khan, Brad Kahl
Resistance to apoptosis is one of the hallmarks of cancer and members of the B-cell lymphoma 2 (BCL-2) family of proteins are central regulators of apoptosis. Many cancers become resistant to chemotherapy and apoptosis by up-regulating BCL-2 and other family members, making these proteins attractive targets for cancer therapy. Venetoclax is an orally administered, small-molecule apoptosis stimulant that targets BCL-2 proteins by acting as a BCL-2 homology domain 3 (BH3) mimetic. The drug is approved in the USA and EU as a monotherapy for the for the treatment of certain patients with chronic lymphocytic leukemia (CLL) and is in phase III clinical development for multiple myeloma (MM), and in phase II or I/II clinical trials for acute myeloid leukemia, and several B-cell malignancies, including diffuse large B-cell lymphoma, Waldenstrom's macroglobulinaemia, follicular lymphoma, and mantle-cell lymphoma...
March 8, 2018: Targeted Oncology
https://www.readbyqxmd.com/read/29507660/flt3-itd-induces-expression-of-pim-kinases-through-stat5-to-confer-resistance-to-the-pi3k-akt-pathway-inhibitors-on-leukemic-cells-by-enhancing-the-mtorc1-mcl-1-pathway
#18
Keigo Okada, Ayako Nogami, Shinya Ishida, Hiroki Akiyama, Cheng Chen, Yoshihiro Umezawa, Osamu Miura
FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. The specific pan-Pim kinase inhibitor AZD1208 as well as PIM447 in combination with the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 cooperatively downregulated the mTORC1/4EBP1 pathway, formation of the eIF4E/eIF4G complex, and Mcl-1 expression leading to activation of Bak and Bax to induce caspase-dependent apoptosis synergistically in these cells...
February 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29459767/mcl-1-and-bcl-x-l-sequestration-of-bak-confers-differential-resistance-to-bh3-only-proteins
#19
Colin Hockings, Amber E Alsop, Stephanie C Fennell, Erinna F Lee, W Douglas Fairlie, Grant Dewson, Ruth M Kluck
The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-xL inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-xL and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim. In contrast, in a Bid and Bak mixture, Bcl-xL preferentially sequestered Bid while Mcl-1 preferentially sequestered Bak...
March 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29454280/8-chrysoeriol-as-a-potential-bcl-2-inhibitor-triggers-apoptosis-of-sw1990-pancreatic-cancer-cells
#20
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...
April 2018: Bioorganic Chemistry
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