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Checkpoint kinase 1

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https://www.readbyqxmd.com/read/29222038/hdac6-inhibition-induces-glioma-stem-cells-differentiation-and-enhances-cellular-radiation-sensitivity-through-the-shh-gli1-signaling-pathway
#1
Wei Yang, Yingying Liu, Ruoling Gao, Hongquan Yu, Ting Sun
The existence of small numbers of stem-like cells, called glioma stem cells (GSCs), in human glioblastoma multiforme (GBM) is responsible for recurrence due to resistance to radiotherapy and chemotherapy. Inhibition of histone deacetylase 6 (HDAC6) enhanced radiosensitivity of cancer cells. However, the effect of inhibiting HDAC6 on stemness and radioresistance of GSCs and its molecular mechanism are largely unknown. In the present study, we found that HDAC6 was upregulated in GSCs comparing to non-stem tumor cells...
December 5, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29221122/checkpoint-kinase-1-inhibition-sensitises-transformed-cells-to-dihydroorotate-dehydrogenase-inhibition
#2
Stéphanie Arnould, Geneviève Rodier, Gisèle Matar, Charles Vincent, Nelly Pirot, Yoann Delorme, Charlène Berthet, Yoan Buscail, Jean Yohan Noël, Simon Lachambre, Marta Jarlier, Florence Bernex, Hélène Delpech, Pierre Olivier Vidalain, Yves L Janin, Charles Theillet, Claude Sardet
Reduction in nucleotide pools through the inhibition of mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) has been demonstrated to effectively reduce cancer cell proliferation and tumour growth. The current study sought to investigate whether this antiproliferative effect could be enhanced by combining Chk1 kinase inhibition. The pharmacological activity of DHODH inhibitor teriflunomide was more selective towards transformed mouse embryonic fibroblasts than their primary or immortalised counterparts, and this effect was amplified when cells were subsequently exposed to PF477736 Chk1 inhibitor...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29220291/emerging-targeted-and-immune-based-therapies-in-sarcoma
#3
Seth M Pollack, Matthew Ingham, Matthew B Spraker, Gary K Schwartz
Soft tissue and bone sarcomas are malignancies of mesenchymal origin, and more than 50 subtypes are defined. For most sarcomas, locally advanced or unresectable disease is still treated with cytotoxic chemotherapy. Recently, our understanding of subtype-specific cancer biology has expanded, and it has revealed distinct molecular alterations responsible for tumor initiation and progression. These findings have motivated the development of targeted therapies that are being evaluated in subtype-specific or biomarker-driven clinical trials...
December 8, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29217118/checkpoints-in-tnf-induced-cell-death-implications-in-inflammation-and-cancer
#4
REVIEW
Alessandro Annibaldi, Pascal Meier
Tumor necrosis factor (TNF) is a proinflammatory cytokine that coordinates tissue homeostasis by regulating cytokine production, cell survival, and cell death. However, how life and death decisions are made in response to TNF is poorly understood. Many inflammatory pathologies are now recognized to be driven by aberrant TNF-induced cell death, which, in most circumstances, depends on the kinase Receptor-interacting serine/threonine-protein kinase 1 (RIPK1). Recent advances have identified ubiquitin (Ub)-mediated phosphorylation of RIPK1 as belonging to crucial checkpoints for cell fate in inflammation and infection...
December 4, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/29216787/mek-inhibitors-under-development-for-treatment-of-non-small-cell-lung-cancer
#5
Chul Kim, Giuseppe Giaccone
The mitogen-activated protein kinase (MAPK) pathway is intimately implicated in the molecular pathogenesis of non-small-cell lung cancer (NSCLC). Aberrant MAPK signaling resulting from the upstream activating mutations converges on mitogen-activated protein kinase kinase 1/2 (MEK1/2), making MEK inhibition an attractive strategy for the treatment of NSCLC. Several MEK inhibitors have demonstrated anticancer activity in patients with NSCLC. Areas covered: In this article, we discuss the biological rationale for the use of MEK inhibitors and summarize the clinical experience with MEK1/2 inhibitors for the treatment of NSCLC, from initial phase I studies to phase II/III studies, both as monotherapy or in combination with other anticancer agents...
December 7, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29213157/immunotherapy-and-gene-therapy-as-novel-treatments-for-cancer
#6
REVIEW
Martha Montserrat Rangel-Sosa, Estuardo Aguilar-Córdova, Augusto Rojas-Martínez
The immune system interacts closely with tumors during the disease development and progression to metastasis. The complex communication between the immune system and the tumor cells can prevent or promote tumor growth. New therapeutic approaches harnessing protective immunological mechanisms have recently shown very promising results. This is performed by blocking inhibitory signals or by activating immunological effector cells directly. Immune checkpoint blockade with monoclonal antibodies directed against the inhibitory immune receptors CTLA-4 and PD-1 has emerged as a successful treatment approach for patients with advanced melanoma...
September 30, 2017: Colombia Médica: CM
https://www.readbyqxmd.com/read/29212506/chromosome-9p-copy-number-gains-involving-pd-l1-are-associated-with-a-specific-proliferation-and-immune-modulating-gene-expression-program-active-across-major-cancer-types
#7
Jan Budczies, Carsten Denkert, Balázs Győrffy, Peter Schirmacher, Albrecht Stenzinger
BACKGROUND: Inhibition of the PD-L1/PD-1 immune checkpoint axis represents one of the most promising approaches of immunotherapy for various cancer types. However, immune checkpoint inhibition is successful only in subpopulations of patients emphasizing the need for powerful biomarkers that adequately reflect the complex interaction between the tumor and the immune system. Recently, recurrent copy number gains (CNG) in chromosome 9p involving PD-L1 were detected in many cancer types including lung cancer, melanoma, bladder cancer, head and neck cancer, cervical cancer, soft tissue sarcoma, prostate cancer, gastric cancer, ovarian cancer, and triple-negative breast cancer...
December 6, 2017: BMC Medical Genomics
https://www.readbyqxmd.com/read/29210298/synthesis-and-preliminary-structure-activity-relationship-study-of-2-aryl-2h-pyrazolo-4-3-c-quinolin-3-ones-as-potential-checkpoint-kinase-1-chk1-inhibitors
#8
Ivana Malvacio, Alberto Cuzzolin, Mattia Sturlese, D Mariano A Vera, E Laura Moyano, Stefano Moro
The serine-threonine checkpoint kinase 1 (Chk1) plays a critical role in the cell cycle arrest in response to DNA damage. In the last decade, Chk1 inhibitors have emerged as a novel therapeutic strategy to potentiate the anti-tumour efficacy of cytotoxic chemotherapeutic agents. In the search for new Chk1 inhibitors, a congeneric series of 2-aryl-2 H-pyrazolo[4,3-c]quinolin-3-one (PQ) was evaluated by in-vitro and in-silico approaches for the first time. A total of 30 PQ structures were synthesised in good to excellent yields using conventional or microwave heating, highlighting that 14 of them are new chemical entities...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/29207595/cdk1-promotes-nascent-dna-synthesis-and-induces-resistance-of-cancer-cells-to-dna-damaging-therapeutic-agents
#9
Hongwei Liao, Fang Ji, Xinwei Geng, Meichun Xing, Wen Li, Zhihua Chen, Huahao Shen, Songmin Ying
Cyclin dependent kinase 1 (CDK1) is essential for cell viability and plays a vital role in many biological events including cell cycle control, DNA damage repair, and checkpoint activation. Here, we identify an unanticipated role for CDK1 in promoting nascent DNA synthesis during S-phase. We report that a short duration of CDK1 inhibition, which does not perturb cell cycle progression, triggers a replication-associated DNA damage response (DDR). This DDR is associated with a disruption of replication fork progression and leads to genome instability...
October 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/29207133/potential-role-of-microrna%C3%A2-223%C3%A2-3p-in-the-tumorigenesis-of-hepatocellular-carcinoma-a-comprehensive-study-based-on-data-mining-and-bioinformatics
#10
Rui Zhang, Li-Jie Zhang, Mei-Ling Yang, Lan-Shan Huang, Gang Chen, Zhen-Bo Feng
The aims of the present study were to examine the potential role of microRNA‑233‑3p (miR)‑223‑3p in the tumorigenesis of hepatocellular carcinoma (HCC), and to investigate its diagnostic accuracy and potential molecular mechanisms. The expression data of miR‑223‑3p in HCC were obtained from the Gene Expression Omnibus (GEO). Data for the precursor miR‑223 were obtained from The Cancer Genome Atlas (TCGA). The diagnostic role of miR‑223‑3p was identified by the receiver operating curve (ROC), and the diagnostic value of miR‑223‑3p in HCC was calculated from qualified reports in the literature...
November 27, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29167438/checkpoint-kinase-1-is-essential-for-normal-b-cell-development-and-lymphomagenesis
#11
Fabian Schuler, Johannes G Weiss, Silke E Lindner, Michael Lohmüller, Sebastian Herzog, Simon F Spiegl, Philipp Menke, Stephan Geley, Verena Labi, Andreas Villunger
Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression in response to DNA damage. Despite its essential function, CHK1 has been identified as a target to kill cancer cells and studies using Chk1 haploinsufficient mice initially suggested a role as tumor suppressor. Here, we report on the key role of CHK1 in normal B-cell development, lymphomagenesis and cell survival. Chemical CHK1 inhibition induces BCL2-regulated apoptosis in primary as well as malignant B-cells and CHK1 expression levels control the timing of lymphomagenesis in mice...
November 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/29164492/advanced-melanoma-current-treatment-options-biomarkers-and-future-perspectives
#12
REVIEW
Elisa A Rozeman, Tim J A Dekker, John B A G Haanen, Christian U Blank
Malignant melanoma accounts for the highest number of deaths from skin cancer, and the prognosis of patients with stage IV disease has historically been poor. Novel insights into both mutations driving tumorigenesis and immune escape mechanisms of these tumors have led to effective treatment options that have revolutionized the treatment of this disease. Targeting the MAPK kinase pathway (with BRAF and MEK inhibitors), as well as targeting checkpoints, such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or programmed death 1 (PD-1), have improved overall survival in patients with late-stage melanoma, and biomarker research for personalized therapy is ongoing for each of these treatment modalities...
November 21, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/29163851/checkpoint-inhibitors-in-endometrial-cancer-preclinical-rationale-and-clinical-activity
#13
REVIEW
Gloria Mittica, Eleonora Ghisoni, Gaia Giannone, Massimo Aglietta, Sofia Genta, Giorgio Valabrega
Context: Treatment of advanced and recurrent endometrial cancer (EC) is still an unmet need for oncologists and gynecologic oncologists. The Cancer Genome Atlas Research Network (TCGA) recently provided a new genomic classification, dividing EC in four subgroups. Two types of EC, the polymerase epsilon (POLE)-ultra-mutated and the microsatellite instability-hyper-mutated (MSI-H), are characterized by a high mutation rate providing the rationale for a potential activity of checkpoint inhibitors...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29163786/axl-inhibition-induces-the-antitumor-immune-response-which-can-be-further-potentiated-by-pd-1-blockade-in-the-mouse-cancer-models
#14
Zhiqiang Guo, Yan Li, Dandan Zhang, Jiaying Ma
Immune checkpoint blockers (ICB) have emerged as a promising new class of antitumor agents which significantly change the treatment landscape in a range of tumors; however, cancer patients benefited from ICB-based immunotherapy remains limited, scoring the need to explore the combination treatments with synergistic mechanisms of action. Axl receptor tyrosine kinase critically involves in the carcinogenesis of multiple cancers due to its dual roles in both promoting cancer invasion and metastasis and suppressing myeloid cell activation and function...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29162720/direct-interactions-of-mitotic-arrest-deficient-1-mad1-domains-with-each-other-and-mad2-conformers-are-required-for-mitotic-checkpoint-signaling
#15
Wenbin Ji, Yibo Luo, Ejaz Ahmad, Song-Tao Liu
As a sensitive signaling system, the mitotic checkpoint ensures faithful chromosome segregation by delaying anaphase onset even when a single kinetochore is unattached to mitotic spindle microtubules. The key signal amplification reaction for the checkpoint is the conformational conversion of "open" mitotic arrest deficient 2 (O-MAD2) into "closed" MAD2 (C-MAD2). The reaction has been suggested to be catalyzed by an unusual catalyst, a MAD1:C-MAD2 tetramer, but how the catalysis is executed and regulated remains elusive...
November 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29160310/cyclin-d-cdk4-kinase-destabilizes-pd-l1-via-cul3-spop-to-control-cancer-immune-surveillance
#16
Jinfang Zhang, Xia Bu, Haizhen Wang, Yasheng Zhu, Yan Geng, Naoe Taira Nihira, Yuyong Tan, Yanpeng Ci, Fei Wu, Xiangpeng Dai, Jianping Guo, Yu-Han Huang, Caoqi Fan, Shancheng Ren, Yinghao Sun, Gordon J Freeman, Piotr Sicinski, Wenyi Wei
Treatments that target immune checkpoints, such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1, have been approved for treating human cancers with durable clinical benefit(1,2). However, many cancer patients fail to respond to anti-PD-1/PD-L1 treatment, and the underlying mechanism(s) is not well understood(3-5). Recent studies revealed that response to PD-1/PD-L1 blockade might correlate with PD-L1 expression levels in tumor cells(6,7). Hence, it is important to mechanistically understand the pathways controlling PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients...
November 16, 2017: Nature
https://www.readbyqxmd.com/read/29157061/the-dna-pol-%C3%AF%C2%B5-stimulatory-activity-of-mrc1-is-modulated-by-phosphorylation
#17
Zhong-Xin Zhang, Jingjing Zhang, Qinhong Cao, Judith L Campbell, Huiqiang Lou
DNA replication checkpoint (Mec1-Mrc1-Rad53 in budding yeast) is an evolutionarily conserved surveillance system to ensure proper DNA replication and genome stability in all eukaryotes. Compared to its well-known function as a mediator of replication checkpoint, the exact role of Mrc1 as a component of normal replication forks remains relatively unclear. In this study, we provide in vitro biochemical evidence to support that yeast Mrc1 is able to enhance the activity of DNA polymerase ϵ (Pol ϵ), the major leading strand replicase...
November 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29153898/the-significance-of-the-pd-l1-expression-in-non-small-cell-lung-cancer-trenchant-double-swords-as-predictive-and-prognostic-markers
#18
REVIEW
Kazuki Takada, Gouji Toyokawa, Fumihiro Shoji, Tatsuro Okamoto, Yoshihiko Maehara
Lung cancer is the leading cause of death due to cancer worldwide. Surgery, chemotherapy, and radiotherapy have been the standard treatment for lung cancer, and targeted molecular therapy has greatly improved the clinical course of patients with non-small-cell lung cancer (NSCLC) harboring driver mutations, such as in epidermal growth factor receptor and anaplastic lymphoma kinase genes. Despite advances in such therapies, the prognosis of patients with NSCLC without driver oncogene mutations remains poor. Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has recently been shown to improve the survival in advanced NSCLC...
October 28, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/29152060/inhibition-of-chk1-sensitizes-ewing-sarcoma-cells-to-the-ribonucleotide-reductase-inhibitor-gemcitabine
#19
Kelli L Goss, Stacia L Koppenhafer, Kathryn M Harmoney, William W Terry, David J Gordon
Ewing sarcoma is a bone and soft tissue sarcoma that occurs in children and young adults. The EWS-FLI1 gene fusion is the driver mutation in most Ewing sarcoma tumors and functions, in part, as an aberrant transcription factor. We recently identified that Ewing sarcoma cells are sensitive to inhibition of ribonucleotide reductase (RNR), which catalyzes the formation of deoxyribonucleotides from ribonucleotides. In this report, we show that Ewing sarcoma cells are sensitive to treatment with clofarabine, which is a nucleoside analogue and allosteric inhibitor of RNR...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29147457/oxidative-stress-delays-prometaphase-metaphase-of-the-first-cleavage-in-mouse-zygotes-via-the-mad2l1-mediated-spindle-assembly-checkpoint
#20
Que Wu, Zhiling Li, Yue Huang, Diting Qian, Man Chen, Wanfen Xiao, Bin Wang
In zygotes, DNA damage delays the first cleavage to enable repair. Our previous study found that 0.03 mM hydrogen peroxide (H2O2) was the minimum concentration required for induction of oxidative DNA damage in mouse zygotes and that this represented the most similar situation to the clinical phenomenon. In this study, we quantified the cleavage rates of cells in blastocysts at different developmental stages, followed by immunofluorescence to detect activation of γ-H2A histone family member X (a marker of DNA damage) in zygotes to confirm that oxidative DNA damage was induced in H2O2-treated zygotes...
2017: Oxidative Medicine and Cellular Longevity
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