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https://www.readbyqxmd.com/read/27912843/the-reduced-concentration-of-citrate-in-cancer-cells-an-indicator-of-cancer-aggressiveness-and-a-possible-therapeutic-target
#1
Icard Philippe, Lincet Hubert
Proliferating cells reduce their oxidative metabolism and rely more on glycolysis, even in the presence of O2 (Warburg effect). This shift in metabolism reduces citrate biosynthesis and diminishes intracellular acidity, both of which promote glycolysis sustaining tumor growth. Because citrate is the donor of acetyl-CoA, its reduced production favors a deacetylation state of proteins favoring resistance to apoptosis and epigenetic changes, both processes contributing to tumor aggressiveness. Citrate levels could be monitored as an indicator of cancer aggressiveness (as already shown in human prostate cancer) and/or could serve as a biomarker for response to therapy...
November 2016: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
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
#2
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/27910887/energy-metabolism-regulated-by-hdac-inhibitor-attenuates-cardiac-injury-in-hemorrhagic-rat-model
#3
Qiyuan Kuai, Chunyan Wang, Yanbing Wang, Weijing Li, Gongqing Zhang, Zhixin Qiao, Min He, Xuanlin Wang, Yu Wang, Xingwei Jiang, Lihua Su, Yuezhong He, Suping Ren, Qun Yu
A disturbance of energy metabolism reduces cardiac function in acute severe hemorrhagic patients. Alternatively, adequate energy supply reduces heart failure and increases survival. However, the approach to regulating energy metabolism conductive to vital organs is limited, and the underlying molecular mechanism remains unknown. This study assesses the ability of histone deacetylase inhibitors (HDACIs) to preserve cardiac energy metabolism during lethal hemorrhagic injury. In the lethally hemorrhagic rat and hypoxic myocardial cells, energy metabolism and heart function were well maintained following HDACI treatment, as evident by continuous ATP production with normal cardiac contraction...
December 2, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27906183/male-sterility-in-mcl-1-flox-mice-is-not-due-to-enhanced-mcl1-protein-stability
#4
Casey Ah-Cann, Maximilien Tailler, Andrew J Kueh, Marco J Herold, Joseph T Opferman, Marie-Liesse Asselin-Labat, Philippe Bouillet
No abstract text is available yet for this article.
December 1, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27903966/pde5-inhibitors-enhance-the-lethality-of-pemetrexed-through-inhibition-of-multiple-chaperone-proteins-and-via-the-actions-of-cyclic-gmp-and-nitric-oxide
#5
Laurence Booth, Jane L Roberts, Andrew Poklepovic, Sarah Gordon, Paul Dent
Phosphodiesterase 5 (PDE5) inhibitors prevent the breakdown of cGMP that results in prolonged protein kinase G activation and the generation of nitric oxide. PDE5 inhibitors enhanced the anti-NSCLC cell effects of the NSCLC therapeutic pemetrexed. [Pemetrexed + sildenafil] activated an eIF2α - ATF4 - CHOP - Beclin1 pathway causing formation of toxic autophagosomes; activated a protective IRE1 - XBP-1 - chaperone induction pathway; and activated a toxic eIF2α - CHOP - DR4 / DR5 / CD95 induction pathway. [Pemetrexed + sildenafil] reduced the expression of c-FLIP-s, MCL-1 and BCL-XL that was blocked in a cell-type -dependent fashion by either over-expression of HSP90 / GRP78 / HSP70 / HSP27 or by blockade of eIF2α-CHOP signaling...
November 26, 2016: Oncotarget
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/27893461/dual-modulation-of-mcl-1-and-mtor-determines-the-response-to-sunitinib
#7
Mohamed Elgendy, Amal Kamal Abdel-Aziz, Salvatore Lorenzo Renne, Viviana Bornaghi, Giuseppe Procopio, Maurizio Colecchia, Ravindran Kanesvaran, Chee Keong Toh, Daniela Bossi, Isabella Pallavicini, Jose Luis Perez-Gracia, Maria Dolores Lozano, Valeria Giandomenico, Ciro Mercurio, Luisa Lanfrancone, Nicola Fazio, Franco Nole, Bin Tean Teh, Giuseppe Renne, Saverio Minucci
Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib...
November 28, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27890615/egr2-is-a-gonadotropin-induced-survival-factor-that-controls-the-expression-of-ier3-in-ovarian-granulosa-cells
#8
Hanyong Jin, Miae Won, Eunkyoung Shin, Hong-Man Kim, Kangseok Lee, Jeehyeon Bae
Pituitary gonadotropins are key hormones that orchestrate the growth and development of ovarian follicles. However, limited information is available on intra-ovarian factors that mediate the actions of gonadotropins. In this study, we identified that the early growth response 2 gene (EGR2) is a gonadotropin-inducible gene in granulosa cells of rats and humans. Analysis of consensus EGR-binding elements (EBEs) showed that the immediate early response 3 gene (IER3) is a novel transcriptional target gene of EGR2 as confirmed by the luciferase assay, electrophoretic mobility-shift assay (EMSA), chromatin immunoprecipitation (ChIP), and western blot analysis...
November 24, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27888063/notch1-signalling-inhibits-apoptosis-of-human-dental-follicle-stem-cells-via-both-the-cytoplasmic-mitochondrial-pathway-and-nuclear-transcription-regulation
#9
Xuepeng Chen, Songying Li, Zhaobin Zeng, Zexu Gu, Yanfang Yu, Feifei Zheng, Yi Zhou, Huiming Wang
Dental follicle stem cells (DFSCs) have been considered as promising candidate cells for periodontal tissue regeneration. Understanding the signalling pathways underlying the apoptosis of DFSCs will facilitate its biomedical application. Here we showed that Notch1 signalling could inhibit DFSCs apoptosis because the constitutive overexpression of the intracellular domain of Notch1 (ICN1) promoted proliferation and suppressed apoptosis by inhibiting cytoplasmic mitochondrial membrane depolarization, cytochrome c release and activation of caspase-9 and caspase-3...
November 22, 2016: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/27878290/-oleocanthal-exerts-anti-melanoma-activities-and-inhibits-stat3-signaling-pathway
#10
Yanli Gu, Jing Wang, Lixin Peng
Tumor angiogenesis, growth and metastasis are three closely related processes. We therefore explored the effects of (-)-oleocanthal (OC) on the three processes in melanoma and investigated underlying mechanisms. In vitro, OC suppressed proliferation, migration, invasion and induced apoptosis in melanoma cells. In addition, OC inhibited proliferation, migration, invasion and tube formation in human umbilical vascular endothelial cells. In vivo, it exhibited potent activity in suppressing tumor growth in a subcutaneous xenograft model...
November 23, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27875574/chidamide-inhibits-aerobic-metabolism-to-induce-pancreatic-cancer-cell-growth-arrest-by-promoting-mcl-1-degradation
#11
Mu He, Zhixin Qiao, Yanbing Wang, Qiyuan Kuai, Changlan Li, Yu Wang, Xingwei Jiang, Xuanlin Wang, Weijing Li, Min He, Suping Ren, Qun Yu
Pancreatic cancer is a fatal malignancy worldwide and urgently requires valid therapies. Previous research showed that the HDAC inhibitor chidamide is a promising anti-cancer agent in pancreatic cancer cell lines. In this study, we elucidate a probable underlying anti-cancer mechanism of chidamide involving the degradation of Mcl-1. Mcl-1 is frequently upregulated in human cancers, which has been demonstrated to participate in oxidative phosphorylation, in addition to its anti-apoptotic actions as a Bcl-2 family member...
2016: PloS One
https://www.readbyqxmd.com/read/27873035/dmfc-3-5-dimethyl-7-h-furo-3-2-g-chromen-7-one-regulates-bim-to-trigger-bax-and-bak-activation-to-suppress-drug-resistant-human-hepatoma
#12
Jun Xiang, Zhe Wang, Qianqian Liu, Xia Li, Jianguo Sun, Kwok-Pui Fung, Feiyan Liu
3,5-Dimethyl-(7)H-furo[3,2-g]chromen-7-one (DMFC) is a coumarin derivative with anti-cancer activity against human hepatoma cells, but the mechanisms underlying DMFC function in cancer suppression is unknown. In this study, we aimed at elucidating the molecular mechanisms underlying DMFC anti-cancer activity and determining whether DMFC is effective in suppression of drug-resistant human hepatocellular carcinoma. We show here that DMFC effectively suppresses both the parent and the multidrug-resistant hepatoma cell growth in vitro and DMFC suppresses hepatoma cell growth at least in part through inducing tumor cell apoptosis...
November 21, 2016: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/27861384/trends-of-triple-negative-breast-cancer-research-2007-2015-a-bibliometric-study
#13
Yiran Wang, Xiao Zhai, Chuan Liu, Ning Wang, Yajie Wang
BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype. However, there have been limited data to evaluate the trend of TNBC research. This study aims to investigate the trend of TNBC research and compare the contribution of research from different regions, organizations, and authors. METHODS: TNBC-related publications from 2007 to 2015 were retrieved from the Web of Science database. Excel 2013 (Redmond, Washington, USA), GraphPad Prism 5 (GraphPad Prism Software Inc...
November 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27856324/mll-af4-binds-directly-to-a-bcl-2-specific-enhancer-and-modulates-h3k27-acetylation
#14
Laura Godfrey, Jon Kerry, Ross Thorne, Emmanouela Repapi, James O J Davies, Marta Tapia, Erica Ballabio, Jim R Hughes, Huimin Geng, Marina Konopleva, Thomas A Milne
Survival rates for children and adults carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis. The most common MLL mutation in ALL is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusion proteins. Previously, we demonstrated that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. Here, we perform a detailed analysis of MLL-AF4 regulation of the entire BCL-2 family...
November 14, 2016: Experimental Hematology
https://www.readbyqxmd.com/read/27847320/inhibition-of-cdk9-induces-apoptosis-and-potentiates-the-effect-of-cisplatin-in-hypopharyngeal-carcinoma-cells
#15
Shengda Cao, Yingyi Yu, Shangren Chen, Dapeng Lei, Shudong Wang, Xinliang Pan, Jun Peng
Myeloid cell leukemia-1 (Mcl-1) plays an important role in survival, chemo- and radioresistance of head and neck squamous cell carcinoma (HNSCC). Cyclin-dependent kinase 9/cyclin T (CDK9) promotes excessive production of multiple pro-survival proteins including Mcl-1, leading to impaired apoptosis of cancer cells. As such, CDK9 is an emerging therapeutic target in cancer therapy. We herein report the first study of targeting CDK9 as a treatment strategy for hypopharyngeal squamous cell carcinoma (HSCC), an aggressive malignancy associated with one of the worst prognoses within HNSCC...
November 12, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27846237/integrated-genomics-identifies-mir-32-mcl-1-pathway-as-a-critical-driver-of-melanomagenesis-implications-for-mir-replacement-and-combination-therapy
#16
Prasun J Mishra, Pravin J Mishra, Glenn Merlino
AIMS: Cutaneous malignant melanoma is among the deadliest human cancers, broadly resistant to most clinical therapies. A majority of patients with BRAFV600E melanomas respond well to inhibitors such as vemurafenib, but all ultimately relapse. Moreover, there are no viable treatment options available for other non-BRAF melanoma subtypes in the clinic. A key to improving treatment options lies in a better understanding of mechanisms underlying melanoma progression, which are complex and heterogeneous...
2016: PloS One
https://www.readbyqxmd.com/read/27825124/acid-ceramidase-is-upregulated-in-aml-and-represents-a-novel-therapeutic-target
#17
Su-Fern Tan, Xin Liu, Todd E Fox, Brian M Barth, Arati Sharma, Stephen D Turner, Andy Awwad, Alden Dewey, Kenichiro Doi, Barbara Spitzer, Mithun Vinod Shah, Samy A F Morad, Dhimant Desai, Shantu Amin, Junjia Zhu, Jason Liao, Jong Yun, Mark Kester, David F Claxton, Hong-Gang Wang, Myles C Cabot, Edward H Schuchman, Ross L Levine, David J Feith, Thomas P Loughran
There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Sphingolipid dysregulation through decreased ceramide levels and elevated sphingosine 1-phosphate (S1P) promotes cancer cell growth and survival. Acid ceramidase (AC) catalyzes ceramide breakdown to sphingosine, the precursor for S1P. We report for the first time that AC is required for AML blast survival. Transcriptome analysis and enzymatic assay show that primary AML cells have high levels of AC expression and activity...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27824316/nickel-chloride-nicl2-in-hepatic-toxicity-apoptosis-g2-m-cell-cycle-arrest-and-inflammatory-response
#18
Hongrui Guo, Hengmin Cui, Jing Fang, Zhicai Zuo, Junliang Deng, Xun Wang, Ling Zhao, Kejie Chen, Jie Deng
Up to now, the precise mechanism of Ni toxicology is still indistinct. Our aim was to test the apoptosis, cell cycle arrest and inflammatory response mechanism induced by NiCl2 in the liver of broiler chickens. NiCl2 significantly increased hepatic apoptosis. NiCl2 activated mitochondria-mediated apoptotic pathway by decreasing Bcl-2, Bcl-xL, Mcl-1, and increasing Bax, Bak, caspase-3, caspase-9 and PARP mRNA expression. In the Fas-mediated apoptotic pathway, mRNA expression levels of Fas, FasL, caspase-8 were increased...
November 5, 2016: Aging
https://www.readbyqxmd.com/read/27821809/trail-induces-pro-apoptotic-crosstalk-between-the-trail-receptor-signaling-pathway-and-trkaiii-in-sh-sy5y-cells-unveiling-a-potential-therapeutic-achilles-heel-for-the-trkaiii-oncoprotein-in-neuroblastoma
#19
Luciana Gneo, Pierdomenico Ruggeri, Lucia Cappabianca, Antonietta Rosella Farina, Natalia Di Ianni, Andrew Reay Mackay
TrkAIII expression in neuroblastoma (NB) associates with advanced stage disease, worse prognosis, post therapeutic relapse, and in NB models TrkAIII exhibits oncogenic activity and promotes chemotherapeutic-resistance. Here, we report a potential therapeutic "Achilles heel" for the TrkAIII oncoprotein in a SH-SY5Y NB model that is characterised by one-way TRAIL-induced, pro-apoptotic crosstalk between the TRAIL receptor signaling pathway and TrkAIII that results in the delayed induction of apoptosis. In TrkAIII SH-SY5Y cells, blocked in the intrinsic apoptosis pathway by elevated constitutive Bcl-2, Bcl-xL and Mcl-1 expression, TRAIL induced delayed caspase-dependent apoptosis via the extrinsic pathway and completely abrogated tumourigenic capacity in vitro...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27821478/mcl-1-depletion-impairs-dna-dsb-repair-and-re-initiation-of-stalled-dna-replication-forks
#20
Abid R Mattoo, Raj K Pandita, Sharmistha Chakraborty, Vijaya Charaka, Kalpana Mujoo, Clayton R Hunt, Tej K Pandita
Myeloid cell leukemia-1 : MCL-1) is a pro-survival BCL-2 protein family member highly expressed in hematopoietic stem cells (HSCs) and regulated by growth factor signals that manifest anti-apoptotic activity. Here we report that depletion of MCL-1, but not its isoform MCL1S, increases genomic instability and cell sensitivity to ionizing radiation (IR) induced death. MCL-1 association with genomic DNA increased post-irradiation and it co-localized with 53BP1 in foci. Post-irradiation, MCL-1 depleted cells exhibited decreased γ-H2AX foci, decreased phosphorylation of ATR and higher levels of residual 53BP1 and RIF1 foci, suggesting DNA DSB repair by homologous recombination (HR) was compromised...
November 7, 2016: Molecular and Cellular Biology
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