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https://www.readbyqxmd.com/read/28741496/targeting-bcl-2-like-proteins-to-kill-cancer-cells
#1
REVIEW
Suzanne Cory, Andrew W Roberts, Peter M Colman, Jerry M Adams
Mutations that impair apoptosis contribute to cancer development and reduce the effectiveness of conventional anti-cancer therapies. These insights and understanding of how the B cell lymphoma (BCL)-2 protein family governs apoptosis have galvanized the search for a new class of cancer drugs that target its pro-survival members by mimicking their natural antagonists, the BCL-2 homology (BH)3-only proteins. Successful initial clinical trials of the BH3 mimetic venetoclax/ABT-199, specific for BCL-2, have led to its recent licensing for refractory chronic lymphocytic leukemia and to multiple ongoing trials for other malignancies...
August 2016: Trends in Cancer
https://www.readbyqxmd.com/read/28739697/z-360-suppresses-tumor-growth-in-mia-paca-2-bearing-mice-via-inhibition-of-gastrin-induced-anti-apoptotic-effects
#2
Yoshihiro Shiomi, Makoto Yoshimura, Kazumasa Kuki, Yuko Hori, Takao Tanaka
BACKGROUND/AIM: The aim of the study was to evaluate the anti-tumor mechanism of Z-360, a gastrin/cholecystokinin-2 receptor (CCK2R) antagonist, in MIA PaCa-2 cells and in a subcutaneous xenograft mice model. MATERIALS AND METHODS: The anti-tumor effects of Z-360 and/or gemcitabine were monitored using a MIA PaCa-2 xenograft model. The effect of Z-360 on apoptosis in the model was examined by TUNEL staining and real-time PCR analysis and the effect in MIA PaCa-2 cells stably expressing human CCK2R was also evaluated by caspase-3/7 activity...
August 2017: Anticancer Research
https://www.readbyqxmd.com/read/28736362/-small-interfering-rna-mediated-monocarboxylate-transporter-1-silencing-enhances-sensitivity-of-nasopharyngeal-carcinoma-hne1-ddp-cells-to-cisplatin-induced-apoptosis
#3
Pei Zhang, Fang Liu, Jiao Gao, Lin-Yan Ma, Xiao-Jin Sun, Hai-Lun Zheng, Hao Liu, Su-Rong Zhao
OBJECTIVE: To investigate the effect of small interfering RNA (siRNA)-mediated silencing of monocarboxylate transporter 1 (MCT1) on the sensitivity of drug-resistant nasopharyngeal carcinoma HNE1/DDP cells to cisplatin (DDP)-induced apoptosis and explore the possible mechanism. METHODS: The expression of MCT1 was analyzed in HNE1 and HNE1/DDP cells and in HNE1/DDP cells transfected with siRNA using Western blot. MTT assay was used to assess the inhibitory effect of different concentrations of DDP alone or in combination with MCT1 siRNA on the proliferation of HNE1/DDP cells...
July 20, 2017: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/28720038/neuroprotective-effect-of-g-14-humanin-on-global-cerebral-ischemia-reperfusion-by-activation-of-socs3-stat3-mcl-1-signal-transduction-pathway-in-rats
#4
Guangsheng Gao, Huaihai Fan, Xiaoying Zhang, Fusen Zhang, Haiyan Wu, Feng Qi, Lei Zhao, Yun Li
OBJECTIVE: Humanin (HN) has been identified to suppress neuron death. Gly(14)-HN (HNG), as a variant of HN, can decrease infarct volume after ischemia/reperfusion (I/R) injury. This study aimed to investigate the neuroprotective mechanism of HNG on global cerebral I/R (GI) in rats. METHODS: Rats were randomly divided into 13 groups: Sham group, GI groups and HNG groups. Both GI group and HNG groups included six time points (1, 3, 6, 12, 24, and 72 h). At 24 h after reperfusion, Nissl staining was used to observe positive neurons, and p-STAT3, MCL-1, SOCS3, Bax and Caspase-3 in different groups were detected by immunohistochemistry...
July 18, 2017: Neurological Research
https://www.readbyqxmd.com/read/28717222/fty720-induces-autophagy-associated-apoptosis-in-human-oral-squamous-carcinoma-cells-in-part-through-a-reactive-oxygen-species-mcl-1-dependent-mechanism
#5
Li-Yuan Bai, Chang-Fang Chiu, Shih-Jiuan Chiu, Po-Chen Chu, Jing-Ru Weng
In this study, we interrogated the mechanism by which the immunosuppressant FTY720 mediates anticancer effects in oral squamous cell carcinoma (OSCC) cells. FTY720 differentially suppressed the viability of the OSCC cell lines SCC4, SCC25, and SCC2095 with IC50 values of 6.1, 6.3, and 4.5 μM, respectively. This antiproliferative effect was attributable to the ability of FTY720 to induce caspase-dependent apoptosis. Mechanistic evidence suggests that FTY720-induced apoptosis was associated with its ability to inhibit Akt-NF-κB signaling, to facilitate the proteasomal degradation of the antiapoptotic protein Mcl-1, and to increase reactive oxygen species (ROS) generation...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28714799/in-silico-approaches-to-identify-novel-myeloid-cell-leukemia-1-mcl-1-inhibitors-for-treatment-of-cancer
#6
Ji-Xia Ren, Cheng-Ping Li, Xiu-Ling Zhou, Xue-Song Cao, Yong Xie
Myeloid cell leukemia-1 (Mcl-1) has been a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to the resistance to current chemotherapeutics. Here, we identified new Mcl-1 inhibitors using a multi-step virtual screening approach. First, based on two different ligand-receptor complexes, 20 pharmacophore models were established by simultaneously using "Receptor-Ligand Pharmacophore Generation" method and manual build feature method, and then carefully validated by a test database...
July 17, 2017: Journal of Biomolecular Structure & Dynamics
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/28713918/endothelial-growth-medium-suppresses-apoptosis-of-mesenchymal-stem-cells-in-vitro-via-decrease-of-mir%C3%A2-29a
#8
Qianqian Wu, Tao Fang, Min Chen, Guoxian Qi
The administration of mesenchymal stem cells (MSCs) in cases of cardiac ischemia/reperfusion injury (IRI) has been associated with a significant reduction of myocardial cell death and an effective improvement in cardiac function. However, one major limiting factor in MSCs transplantation therapy is the low survival rate of the transplanted cells. The present study aimed to demonstrate that human amnion‑derived mesenchymal stem cells (hAMSCs) cultured with endothelial growth medium (EGM‑2) exhibited reduced apoptosis when exposed to serum‑free and hypoxic conditions; and that the expression of microRNA (miR)‑29a decreased significantly...
September 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28712306/targeting-intrinsic-apoptosis-and-other-forms-of-cell-death-by-bh3-mimetics-in-glioblastoma
#9
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/28711932/the-pan-bcl-2-blocker-obatoclax-gx15-070-and-the-pi3-kinase-mtor-inhibitor-bez235-produce-cooperative-growth-inhibitory-effects-in-all-cells
#10
Gabriele Stefanzl, Daniela Berger, Sabine Cerny-Reiterer, Katharina Blatt, Gregor Eisenwort, Wolfgang R Sperr, Gregor Hoermann, Karin Lind, Alexander W Hauswirth, Peter Bettelheim, Heinz Sill, Junia V Melo, Ulrich Jäger, Peter Valent
Acute lymphoblastic leukemia (ALL) is characterized by leukemic expansion of lymphoid blasts in hematopoietic tissues. Despite improved therapy only a subset of patients can be cured. Therefore, current research is focusing on new drug-targets. Members of the BCL-2 family and components of the PI3-kinase/mTOR pathway are critically involved in the regulation of growth and survival of ALL cells. We examined the effects of the pan-BCL-2 blocker obatoclax and the PI3-kinase/mTOR-inhibitor BEZ235 on growth and survival of ALL cells...
June 28, 2017: Oncotarget
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
#11
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/28698410/combination-treatment-of-rad001-and-bez235-exhibits-synergistic-antitumor-activity-via-down-regulation-of-p-4e-bp1-mcl-1-in-small-cell-lung-cancer
#12
Bo Hong, Huogang Wang, Ke Deng, Wei Wang, Haiming Dai, Vivian Wai Yan Lui, Wenchu Lin
Small cell lung cancer (SCLC) is a highly malignant cancer with few targeted therapies. In the study, by mining the Cancer Cell Line Encyclopedia (CCLE) database, we found that PI3K/AKT/mTOR pathway was aberrant in 92% of SCLC cell lines. Moreover, we found that the phosphorylation level of 4E-BP1 was significantly correlated with SCLC sensitivity to RAD001 (mTOR inhibitor) and BEZ235 (PI3K/mTOR dual inhibitor). Combination of RAD001 and BEZ235 synergistically inhibited the growth of SCLC cells, which was accompanied by enhanced induction of cell cycle arrest and apoptosis...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28696828/small-molecule-inhibitor-tw-37-is-tolerable-and-synergistic-with-chemotherapy-in-nasopharyngeal-carcinoma
#13
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/28696369/2-5-dihydroxyacetophenone-induces-apoptosis-of-multiple-myeloma-cells-by-regulating-the-mapk-activation-pathway
#14
Jeong-Hyeon Ko, Jae Hwi Lee, Sang Hoon Jung, Seok-Geun Lee, Arunachalam Chinnathambi, Sulaiman Ali Alharbi, Woong Mo Yang, Jae-Young Um, Gautam Sethi, Kwang Seok Ahn
2,5-Dihydroxyacetophenone (DHAP) is an active compound obtained from Radix rehmanniae preparata, which is widely used as a herbal medicine in many Asian countries. DHAP has been found to possess anti-inflammatory, anti-anxiety, and neuroprotective qualities. For the present study, we evaluated the anti-cancer effects of DHAP on multiple myeloma cells. It was discovered that DHAP downregulated the expression of oncogenic gene products like Bcl-xl, Bcl-2, Mcl-1, Survivin, Cyclin D1, IAP-1, Cyclin E, COX-2, and MMP-9, and upregulated the expression of Bax and p21 proteins, consistent with the induction of G2/M phase cell cycle arrest and apoptosis in U266 cells...
July 11, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28692117/clinical-significance-and-expression-of-puma-mcl-1-and-p53-in-human-renal-cell-carcinoma-and-para-carcinoma-tissues
#15
H B Xia, H W Cui, L Su, Z H Zhang, X Y Yang, S Q Ning, X L Su
We investigated the expression level of p53 upregulated modulator of apoptosis (PUMA), myeloid cell leukemia-I (MCL-1), and p53 in renal cell carcinoma (RCC) and para-carcinoma tissues, as well as their clinical significance. The expression levels of PUMA, MCL-1, and p53 in RCC and para-carcinoma tissues were measured using immunohistochemical and quantitative real-time PCR methods. Correlations between protein expression and pathological characteristics were analyzed. Renal clear cell carcinoma showed elevated MCL-1 and p53 protein expression (P > 0...
July 6, 2017: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/28689299/4-o-methylhonokiol-protects-from-alcohol-carbon-tetrachloride-induced-liver-injury-in-mice
#16
Eleonora Patsenker, Andrea Chicca, Vanessa Petrucci, Sheida Moghadamrad, Andrea de Gottardi, Jochen Hampe, Jürg Gertsch, Nasser Semmo, Felix Stickel
Alcoholic liver disease (ALD) is a leading cause of liver cirrhosis, liver cancer, and related mortality. The endocannabinoid system contributes to the development of chronic liver diseases, where cannabinoid receptor 2 (CB2) has been shown to have a protecting role. Thus, here, we investigated how CB2 agonism by 4'-O-methylhonokiol (MHK), a biphenyl from Magnolia grandiflora, affects chronic alcohol-induced liver fibrosis and damage in mice. A combination of alcohol (10% vol/vol) and CCl4 (1 ml/kg) was applied to C57BL/6 mice for 5 weeks...
July 8, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/28687276/nap1l1-regulates-nf-%C3%AE%C2%BAb-signaling-pathway-acting-on-anti-apoptotic-mcl-1-gene-expression
#17
Toshiaki Tanaka, Yasukazu Hozumi, Mitsuyoshi Iino, Kaoru Goto
Nuclear factor-κB (NF-κB) participates in apoptosis signaling pathway under various pathophysiological conditions. It exerts transcriptional control on the anti-apoptotic Bcl-2 family, such as Bcl-2, Bcl-xl, and Mcl-1, which act on the mitochondrial outer membrane. Previously, we described that NF-κB is negatively regulated by diacylglycerol kinase ζ (DGKζ), an enzyme that phosphorylates a lipid second messenger diacylglycerol. DGKζ downregulation enhances inhibitors of NF-κB α (IκBα) degradation and p65 subunit phosphorylation, leading to enhanced NF-κB transcriptional activity...
July 4, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28686074/simultaneous-targeting-of-atm-and-mcl-1-increases-cisplatin-sensitivity-of-cisplatin-resistant-non-small-cell-lung-cancer
#18
Fuquan Zhang, Mingjing Shen, Li Yang, Xiaodong Yang, Ying Tsai, Peter C Keng, Yongbing Chen, Soo Ok Lee, Yuhchyau Chen
Development of cisplatin-resistance is an obstacle in non-small cell lung cancer (NSCLC) therapeutics. To investigate which molecules are associated with cisplatin-resistance, we analyzed expression profiles of several DNA repair and anti-apoptosis associated molecules in parental (A549P and H157P) and cisplatin-resistant (A549CisR and H157CisR) NSCLC cells. We detected constitutively upregulated nuclear ATM and cytosolic Mcl-1 molecules in cisplatin-resistant cells compared to parental cells. Increased levels of phosphorylated ATM (p-ATM) and its downstream molecules, CHK2, p-CHK2, p-53, and p-p53 were also detected in cisplatin-resistant cells, suggesting an activation of ATM signaling in these cells...
July 7, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28684899/virtual-screening-for-potential-inhibitors-of-mcl-1-conformations-sampled-by-normal-modes-molecular-dynamics-and-nuclear-magnetic-resonance
#19
Yitav Glantz-Gashai, Tomer Meirson, Eli Reuveni, Abraham O Samson
Myeloid cell leukemia-1 (Mcl-1) is often overexpressed in human cancer and is an important target for developing antineoplastic drugs. In this study, a data set containing 2.3 million lead-like molecules and a data set of all the US Food and Drug Administration (FDA)-approved drugs are virtually screened for potential Mcl-1 ligands using Protein Data Bank (PDB) ID 2MHS. The potential Mcl-1 ligands are evaluated and computationally docked on to three conformation ensembles generated by normal mode analysis (NMA), molecular dynamics (MD), and nuclear magnetic resonance (NMR), respectively...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28681695/mcl-1-suppresses-abasic-site-repair-following-bile-acid-induced-hepatic-cellular-dna-damage
#20
Haiyang Yu, Xiaoqing Zhang, Ren Liu, Hui Li, Xiaolong Xiao, Yuzheng Zhou, Chaoying Wei, Manyi Yang, Mingmei Liao, Jinfeng Zhao, Zanxian Xia, Qiande Liao
In cholestasis, increases in bile acid levels result in the generation of reactive oxygen species and the induction of DNA damage and mutation. It is believed that bile acid accumulation is associated with liver tumorigenesis. However, the mechanism that underpins this phenomenon remains to be elucidated. Mcl-1, which is overexpressed in hepatic cells, is a pro-survival member of the Bcl-2 family. In this study, we observed that Mcl-1 potently suppresses the repair of bile acid-induced abasic (apurinic/apyrimidinic) sites in DNA lesions...
July 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
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