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Cdk4 inhibitor

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https://www.readbyqxmd.com/read/28926061/network-based-modelling-and-percolation-analysis-of-conformational-dynamics-and-activation-in-the-cdk2-and-cdk4-proteins-dynamic-and-energetic-polarization-of-the-kinase-lobes-may-determine-divergence-of-the-regulatory-mechanisms
#1
G M Verkhivker
The overarching goal of delineating molecular principles underlying differentiation of the activation mechanisms in cyclin-dependent kinases (CDKs) is important for understanding regulatory divergences among closely related kinases which can be exploited in drug discovery of targeted and allosteric inhibitors. To systematically characterize dynamic, energetic and network signatures of the activation mechanisms, we combined atomistic simulations and elastic network modeling with the analysis of the residue interaction networks and rigidity decomposition of the CDK2-cyclin A and CDK4-cyclin D1/D3 complexes...
September 19, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28923602/cell-wall-mannoprotein-of-candida-albicans-induces-cell-cycle-alternation-and-inhibits-apoptosis-of-hacat-cells-via-nf-%C3%AE%C2%BAb-signal-pathway
#2
Yang Han, Hang-Hang Jiang, Yu-Jing Zhang, Xing-Jia Hao, Yu-Zhe Sun, Rui-Qun Qi, Hong-Duo Chen, Xing-Hua Gao
Candida albicans (C. albicans) is a commensal organism in human and a well-known dimorphic opportunistic pathogenic fungus. Though plenty of researches on the pathogenesis of C. albicans have been performed, the mechanism is not fully understood. The cell wall components of C. albicans have been documented to play important roles in its pathogenic processes. To further study the infectious mechanism of C. albicans, we investigated the potential functional role of its cell wall mannoprotein in cell cycle and apoptosis of HaCaT cells...
September 15, 2017: Microbial Pathogenesis
https://www.readbyqxmd.com/read/28923217/current-challenges-in-the-management-of-breast-cancer-brain-metastases
#3
REVIEW
Ciara C O'Sullivan, Nicole N Davarpanah, Jame Abraham, Susan E Bates
Approximately 50% of patients with advanced human epidermal growth factor 2 (HER2)-positive breast cancer and triple-negative breast cancer (TNBC) ultimately develop breast cancer brain metastases (BCBM), which are associated with significant morbidity and mortality. The advent of HER2-directed therapy resulted in greatly improved survival outcomes, but unfortunately at the price of an increased cumulative incidence of BCBM. We review challenges in the management of BCBM, and potential treatment strategies, including novel agents such as poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors (olaparib, veliparib), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib, abemaciclib), and taxane derivatives (eg, ANG1005 and TPI-287)...
April 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/28922542/a-diphenyldiselenide-derivative-induces-autophagy-via-jnk-in-htb-54-lung-cancer-cells
#4
Marta Díaz, Roncesvalles González, Daniel Plano, Juan Antonio Palop, Carmen Sanmartín, Ignacio Encío
Symmetric aromatic diselenides are potential anticancer agents with strong cytotoxic activity. In this study, the in vitro anticancer activities of a novel series of diarylseleno derivatives from the diphenyldiselenide (DPDS) scaffold were evaluated. Most of the compounds exhibited high efficacy for inducing cytotoxicity against different human cancer cell lines. DPDS 2, the compound with the lowest mean GI50 value, induced both caspase-dependent apoptosis and arrest at the G0 /G1 phase in acute lymphoblastic leucemia CCRF-CEM cells...
September 18, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28918692/the-cyclin-dependent-kinase-4-6-inhibitor-abemaciclib-exerts-dose-dependent-cytostatic-and-cytocidal-effects-and-induces-autophagy-in-multiple-myeloma-cells
#5
Noriyoshi Iriyama, Hirotsugu Hino, Shota Moriya, Masaki Hiramoto, Yoshihiro Hatta, Masami Takei, Keisuke Miyazawa
The D-type cyclin (CCND)-cyclin-dependent kinase 4/6 (CDK4/6) complex has been implicated in multiple myeloma development. We investigated the biological activity of CDK4/6 inhibitor abemaciclib on cell growth and survival in three myeloma cell lines, KMS-12-PE, RPMI 8226, and IM-9. Abemaciclib inhibited myeloma cell growth in a dose-dependent manner in all cell lines, with significant differences seen at a concentration of 320 nM. Treatment with 1 μM abemaciclib increased the fraction of cells in the G0/G1 phase and decreased the fraction in the S-G2/M phases...
September 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28915557/loss-of-p16-ink4a-stimulates-aberrant-mitochondrial-biogenesis-through-a-cdk4-rb-independent-pathway
#6
Ethika Tyagi, Bin Liu, Chelsea Li, Tong Liu, Jared Rutter, Douglas Grossman
The tumor suppressor p16INK4A (p16) inhibits cell cycle progression through the CDK4/Rb pathway. We have previously shown that p16 regulates cellular oxidative stress, independent of its role in cell cycle control. We investigated whether loss of p16 had a direct impact on the mitochondria. We found that p16-null primary mouse fibroblasts (PMFs) displayed increased mitochondrial mass and expression of mitochondrial respiratory subunit proteins compared to wild-type (WT) PMFs. These findings in p16-null PMFs were associated with increased expression of the mitochondrial biogenesis transcription factors PRC and TFAM...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28911822/structural-insights-of-cyclin-dependent-kinases-implications-in-design-of-selective-inhibitors
#7
REVIEW
Sourav Kalra, Gaurav Joshi, Anjana Munshi, Raj Kumar
There are around 20 Cyclin-dependent kinases (CDKs) known till date, and various research groups have reported their role in different types of cancer. The X-ray structures of some CDKs especially CDK2 was exploited in the past few years, and several inhibitors have been found, e.g., flavopiridol, indirubicin, roscovitine, etc., but due to the specificity issues of these inhibitors (binding to all CDKs), these were called as pan inhibitors. The revolutionary outcome of palbociclib in 2015 as CDK4/6 inhibitor added a new charm to the specific inhibitor design for CDKs...
September 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28905990/the-mtor-kinase-inhibitor-everolimus-synergistically-enhances-the-anti-tumor-effect-of-the-bruton-s-tyrosine-kinase-btk-inhibitor-pls-123-on-mantle-cell-lymphoma
#8
Jiao Li, Xiaogan Wang, Yan Xie, Zhitao Ying, Weiping Liu, Lingyan Ping, Chen Zhang, Zhengying Pan, Ning Ding, Yuqin Song, Jun Zhu
Mantle cell lymphoma (MCL) is an aggressive and incurable malignant disease. Despite of general chemotherapy, relapse and mortality are common, highlighting the need for the development of novel targeted drugs or combination of therapeutic regimens. Recently, several drugs that target the B-cell receptor (BCR) signaling pathway, especially the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicate that pharmacological inhibition of BCR pathway holds promise in MCL treatment...
September 14, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28903422/cdk4-6-inhibition-is-more-active-against-the-glioblastoma-proneural-subtype
#9
Ming Li, Aizhen Xiao, Desiree Floyd, Inan Olmez, Jeongwu Lee, Jakub Godlewski, Agnieszka Bronisz, Krishna P L Bhat, Erik P Sulman, Ichiro Nakano, Benjamin Purow
Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17˜92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28888575/fascaplysin-inhibit-ovarian-cancer-cell-proliferation-and-metastasis-through-inhibiting-cdk4
#10
Shuo Chen, Xue Guan, Li-Li Wang, Bo Li, Xiu-Bo Sang, Yao Liu, Yang Zhao
OBJECTIVE: Cyclin-dependent kinases (CDKs) are important regulators of the cell cycle; previous studies have shown that misregulation of CDK4 (cyclin-dependent kinase 4) activity can lead to cancer. The present study investigated the anti-tumor effects of a highly selective CDK4 inhibitor fascaplysin in ovarian carcinoma cell lines. MATERIALS AND METHODS: In our study, cell proliferation, cell cycle, cell apoptosis, cell invasion, and cell migration relative assays were performed in ovarian cancer cell lines A2780 and OVCAR3 in the presence of different concentrations of fascaplysin...
September 6, 2017: Gene
https://www.readbyqxmd.com/read/28875723/ribociclib-for-post-menopausal-women-with-hr-her2-advanced-or-metastatic-breast-cancer
#11
Mark L Zangardi, Laura M Spring, Gayle C Blouin, Aditya Bardia
The introduction of CDK4/6 inhibitors, such as ribociclib, has changed the treatment landscape for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer. As first-line treatment of HR+/HER2- MBC, the addition of a CDK4/6 inhibitor to an aromatase inhibitor improves progression-free survival compared to an aromatase inhibitor alone. Areas covered: In this drug profile, we review the current market for HR+/HER2- MBC, as well as the characteristics, mechanism, pharmacology, pharmacodynamics, pharmacokinetics, metabolism, clinical efficacy, toxicities, monitoring, and dosing modification of the CDK4/6 inhibitor ribociclib...
September 6, 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28869970/competing-memories-of-mitogen-and-p53-signalling-control-cell-cycle-entry
#12
Hee Won Yang, Mingyu Chung, Takamasa Kudo, Tobias Meyer
Regulation of cell proliferation is necessary for immune responses, tissue repair, and upkeep of organ function to maintain human health. When proliferating cells complete mitosis, a fraction of newly born daughter cells immediately enter the next cell cycle, while the remaining cells in the same population exit to a transient or persistent quiescent state. Whether this choice between two cell-cycle pathways is due to natural variability in mitogen signalling or other underlying causes is unknown. Here we show that human cells make this fundamental cell-cycle entry or exit decision based on competing memories of variable mitogen and stress signals...
September 6, 2017: Nature
https://www.readbyqxmd.com/read/28866094/palbociclib-a-selective-cdk4-6-inhibitor-enhances-the-effect-of-selumetinib-in-ras-driven-non-small-cell-lung-cancer
#13
Jianya Zhou, Shumeng Zhang, Xi Chen, Xianan Zheng, Yinan Yao, Guohua Lu, Jianying Zhou
KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC). Resistance to MEK inhibitor monotherapy develops through a variety of mechanisms. CDK4 was reported to have a synthetic lethal interaction with KRAS. In this study, we demonstrated the combination effects of the MEK inhibitor selumetinib and the CDK4/6 inhibitor palbociclib in RAS-driven NSCLC. In vitro, cell lines with CDKN2A mutations were insensitive to selumetinib. We used siRNA and pharmacologic inhibition of CDK4 and found that the combination of selumetinib and palbociclib synergistically inhibited RAS-driven NSCLC cases with CDKN2A mutations but not those with wild type CDKN2A...
September 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28864481/cdk4-6-inhibitors-induce-antitumor-immunity
#14
(no author information available yet)
CDK4/6 inhibitors not only induce cell-cycle arrest but also promote antitumor immunity by stimulating the production of type III interferons, which enhance tumor antigen presentation, and suppress regulatory T cells. The immune effects of these drugs provide a rationale for combining CDK4/6 inhibitors with checkpoint blockade agents.
September 1, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28861689/superactive-human-leptin-antagonist-shla-triple-lan1-and-quadruple-lan2-leptin-mutein-as-a-promising-treatment-for-human-folliculoma
#15
E Fiedor, E L Gregoraszczuk
PURPOSE: There are no data showing a direct correlation between obesity and increased blood leptin levels with folliculoma. Moreover, folliculoma is not the best studied among other ovarian cancer types. We investigated whether oestradiol can modulate ObR expression in some oestrogen-responsive tissues and that leptin exerts its activity not only via the leptin receptor but also through cross talk with other signalling systems. We hypothesise that blocking ObR expression could be a novel treatment for gonadal ovarian cancer...
August 31, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28860801/nras-mutant-melanoma-current-challenges-and-future-prospect
#16
REVIEW
Eva Muñoz-Couselo, Ester Zamora Adelantado, Carolina Ortiz, Jesús Soberino García, José Perez-Garcia
Melanoma is one of the most common cutaneous cancers worldwide. Activating mutations in RAS oncogenes are found in a third of all human cancers and NRAS mutations are found in 15%-20% of melanomas. The NRAS-mutant subset of melanoma is more aggressive and associated with poorer outcomes, compared to non-NRAS-mutant melanoma. Although immune checkpoint inhibitors and targeted therapies for BRAF-mutant melanoma are transforming the treatment of metastatic melanoma, the ideal treatment for NRAS-mutant melanoma remains unknown...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28855512/atrx-is-a-regulator-of-therapy-induced-senescence-in-human-cells
#17
Marta Kovatcheva, Will Liao, Mary E Klein, Nicolas Robine, Heather Geiger, Aimee M Crago, Mark A Dickson, William D Tap, Samuel Singer, Andrew Koff
Senescence is a state of stable cell cycle exit with important implications for development and disease. Here, we demonstrate that the chromatin remodeling enzyme ATRX is required for therapy-induced senescence. ATRX accumulates in nuclear foci and is required for therapy-induced senescence in multiple types of transformed cells exposed to either DNA damaging agents or CDK4 inhibitors. Mobilization into foci depends on the ability of ATRX to interact with H3K9me3 histone and HP1. Foci form soon after cells exit the cell cycle, before other hallmarks of senescence appear...
August 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28855436/effects-of-sorafenib-and-an-adenylyl-cyclase-activator-on-in-vitro-growth-of-well-differentiated-thyroid-cancer-cells
#18
Aya Sawa, Tomohiro Chiba, Jun Ishii, Hiroyuki Yamamoto, Hisato Hara, Hiroshi Kamma
Well-differentiated thyroid carcinomas have driver mutations involving growth factor receptor-tyrosine kinases (RTKs) or their intracellular signaling pathway, that is, the mitogen-activated protein kinase (MAPK) pathway. Sorafenib is a multikinase inhibitor of RTKs and the MAPK pathway and has recently been used for the treatment of unresectable well-differentiated thyroid carcinoma. In normal thyroid follicular cells, stimulation of the thyroid-stimulating hormone (TSH) receptor activates the cyclic adenosine monophosphate (cAMP) pathway and promotes cell growth as well as hormonal secretion...
August 31, 2017: Endocrine Journal
https://www.readbyqxmd.com/read/28849241/a-novel-chalcone-based-molecule-bdp-inhibits-mda%C3%A2-mb%C3%A2-231-triple-negative-breast-cancer-cell-growth-by-suppressing-hsp90-function
#19
Yong Jin Oh, Young Ho Seo
Triple-negative breast cancer (TNBC) is a molecularly diverse and heterogeneous disease and the molecular heterogeneity of TNBC increases the difficulty in improving survival rates. To date, therapeutic approaches for the treatment of TNBC such as hormonal chemotherapy and trastuzumab-based therapy have been limited by the lack of target receptors such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2), emphasizing the urgent need for identifying new therapeutic options...
October 2017: Oncology Reports
https://www.readbyqxmd.com/read/28844099/epigenetic-silencing-of-prss3-provides-growth-and-metastasis-advantage-for-human-hepatocellular-carcinoma
#20
Bonan Lin, Xiaomeng Zhou, Shuye Lin, Xiaoyue Wang, Meiying Zhang, Baoping Cao, Yan Dong, Shuai Yang, Ji Ming Wang, Mingzhou Guo, Jiaqiang Huang
Protease, serine, 3 (PRSS3), a member of the trypsin family of serine proteases, has been shown to be aberrantly expressed in several cancer types and to play important roles in tumor progression and metastasis. However, the expression and function of PRSS3 gene in hepatocellular carcinoma (HCC) remain unclear. Here we found that PRSS3 expression was decreased in human HCC cell lines and HCC surgical specimens. This was associated with intragenic methylation of PRSS3 gene. Treatment with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine and/or histone deacetylase inhibitor trichostatin A restored PRSS3 expression in HCC cell lines...
August 26, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
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