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https://www.readbyqxmd.com/read/28931335/activation-of-erk-signaling-by-src-family-kinases-sfks-in-drg-neurons-contributes-to-hydrogen-peroxide-h2o2-induced-thermal-hyperalgesia
#1
Ajeet Kumar Singh, Manjula Vinayak
Concomitant generation of reactive oxygen species during tissue inflammation has been recognized as a major factor for development and maintenance of hyperalgesia, out of which H2O2 is the major player. However, molecular mechanism of H2O2 induced hyperalgesia is still obscure. The aim of present study is to analyze the mechanism of H2O2 induced hyperalgesia in rats. Intraplantar injection of H2O2 (5, 10 and 20 µmoles/paw) induced a significant thermal hyperalgesia in the hind paw, confirmed by increased c-Fos activity in dorsal horn of spinal cord...
September 21, 2017: Free Radical Research
https://www.readbyqxmd.com/read/28928905/fucoxanthin-a-marine-carotenoid-attenuates-%C3%AE-amyloid-oligomer-induced-neurotoxicity-possibly-via-regulating-the-pi3k-akt-and-the-erk-pathways-in-sh-sy5y-cells
#2
Jiajia Lin, Jie Yu, Jiaying Zhao, Ke Zhang, Jiachen Zheng, Jialing Wang, Chunhui Huang, Jingrong Zhang, Xiaojun Yan, William H Gerwick, Qinwen Wang, Wei Cui, Shan He
Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by neurofibrillary tangles, synaptic impairments, and loss of neurons. Oligomers of β-amyloid (Aβ) are widely accepted as the main neurotoxins to induce oxidative stress and neuronal loss in AD. In this study, we discovered that fucoxanthin, a marine carotenoid with antioxidative stress properties, concentration dependently prevented Aβ oligomer-induced increase of neuronal apoptosis and intracellular reactive oxygen species in SH-SY5Y cells...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28928884/anti-melanoma-activities-of-haspin-inhibitor-chr-6494-deployed-as-a-single-agent-or-in-a-synergistic-combination-with-mek-inhibitor
#3
Lili Han, Peiling Wang, Yang Sun, Sijing Liu, Jun Dai
Background: Melanoma is a heterogeneous malignancy that presents an immense challenge in therapeutic development. Recent approaches targeting the oncogenic MAP kinase pathways have shown tremendous improvement in the overall survival of patients with advanced melanoma. However, there is still an urgent need for identification of new strategies to overcome drug resistances and to improve therapeutic efficacy. Haspin (Haploid Germ Cell-Specific Nuclear Protein Kinase) belongs to a selected group of mitotic kinases and is required for normal mitosis progression...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28928846/mek-inhibitor-enhances-sensitivity-to-chemotherapeutic-drugs-in-multidrug-resistant-hepatocellular-carcinoma-cells
#4
Qingliang Meng, Xiaoqi He, Guangwei Xie, Qingzhong Tian, Xiaogang Shu, Jin Li, Yong Xiao
The aim of the present study was to investigate the association between the mitogen-activated protein kinase (MAPK) signal transduction pathway and multidrug resistance in hepatocellular carcinoma cells. A Cell Counting Kit-8 assay was used to determine the drug sensitivity of HepG2 and HepG2/ADM hepatocellular carcinoma cell lines in combination with the MAPK/extracellular-signal-regulated kinase kinase (MEK) inhibitor U0126. Flow cytometry was used to analyze the rate of apoptosis. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to determine P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) mRNA expression following treatment with various concentrations of U0126...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28928360/tumor-associated-b-cells-induce-tumor-heterogeneity-and-therapy-resistance
#5
Rajasekharan Somasundaram, Gao Zhang, Mizuho Fukunaga-Kalabis, Michela Perego, Clemens Krepler, Xiaowei Xu, Christine Wagner, Denitsa Hristova, Jie Zhang, Tian Tian, Zhi Wei, Qin Liu, Kanika Garg, Johannes Griss, Rufus Hards, Margarita Maurer, Christine Hafner, Marius Mayerhöfer, Georgios Karanikas, Ahmad Jalili, Verena Bauer-Pohl, Felix Weihsengruber, Klemens Rappersberger, Josef Koller, Roland Lang, Courtney Hudgens, Guo Chen, Michael Tetzlaff, Lawrence Wu, Dennie Tompers Frederick, Richard A Scolyer, Georgina V Long, Manashree Damle, Courtney Ellingsworth, Leon Grinman, Harry Choi, Brian J Gavin, Margaret Dunagin, Arjun Raj, Nathalie Scholler, Laura Gross, Marilda Beqiri, Keiryn Bennett, Ian Watson, Helmut Schaider, Michael A Davies, Jennifer Wargo, Brian J Czerniecki, Lynn Schuchter, Dorothee Herlyn, Keith Flaherty, Meenhard Herlyn, Stephan N Wagner
In melanoma, therapies with inhibitors to oncogenic BRAF(V600E) are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28927233/fibroblast-growth-factor-2-mediated-fgfr-erk-signaling-supports-maintenance-of-cancer-stem-like-cells-in-esophageal-squamous-cell-carcinoma
#6
Osamu Maehara, Goki Suda, Mitsuteru Natsuizaka, Shunsuke Ohnishi, Yoshito Komatsu, Fumiyuki Sato, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Tomoe Shimazaki, Megumi Kimura, Ayaka Asano, Yoshiyuki Fujimoto, Shinya Ohashi, Shingo Kagawa, Hideaki Kinugasa, Seiji Naganuma, Kelly A Whelan, Hiroshi Nakagawa, Koji Nakagawa, Hiroshi Takeda, Naoya Sakamoto
In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT)...
September 13, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28927059/matrine-inhibits-cell-proliferation-and-induces-apoptosis-of-human-rhabdomyosarcoma-cells-via-downregulation-of-the-extracellular-signal-regulated-kinase-pathway
#7
Penghui Yan, Zongqiang Huang, Junbo Zhu
Matrine, extracted from the Chinese traditional medicine Sophorae flavescentis, has been demonstrated to exhibit antitumor effects on numerous types of cancer in vivo and in vitro with low toxicity. However, its antitumor mechanism in rhabdomyosarcoma (RMS) cells remains unclear. In the present study, the antitumor effects of matrine and its underlying mechanisms in RMS were investigated in vitro. The results demonstrated that matrine inhibited cell proliferation, migration and invasion, and induced apoptosis of RMS cells in a dose-dependent manner...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28923937/direct-engagement-of-the-pi3k-pathway-by-mutant-kit-dominates-oncogenic-signaling-in-gastrointestinal-stromal-tumor
#8
Benedikt Bosbach, Ferdinand Rossi, Yasemin Yozgat, Jennifer Loo, Jennifer Q Zhang, Georgina Berrozpe, Katherine Warpinski, Imke Ehlers, Darren Veach, Andrew Kwok, Katia Manova, Cristina R Antonescu, Ronald P DeMatteo, Peter Besmer
Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic Kit(V558Δ) mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant Kit(V558Δ/+) mice, double-mutant Kit(V558Δ;Y567F/Y567F) knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28923853/adaptation-to-tki-treatment-reactivates-erk-signaling-in-tyrosine-kinase-driven-leukemias-and-other-malignancies
#9
Joshua K Bruner, Hayley S Ma, Li Li, Alice Can Ran Qin, Michelle A Rudek, Richard J Jones, Mark J Levis, Keith W Pratz, Christine A Pratilas, Donald Small
FLT3 tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia. We hypothesized that FLT3/ITD leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated and anti-leukemia effects were more pronounced compared to either drug alone...
September 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28923043/rosmarinic-acid-induces-rabbit-articular-chondrocyte-differentiation-by-decreases-matrix-metalloproteinase-13-and-inflammation-by-upregulating-cyclooxygenase-2-expression
#10
Seong-Hui Eo, Song Ja Kim
BACKGROUND: Matrix metalloproteinases (MMPs) are known to play an important role in the degradation of the extracellular matrix and the pathological progression of osteoarthritis (OA). The natural polyphenolic compound rosmarinic acid (Ros. A) has been shown to suppress the inhibitory activity of matrix metalloproteinases (MMPs). However, the effects of Ros. A on OA have not been investigated. METHODS: In the current study, primary articular chondrocytes were cultured from rabbit articular cartilage and treated with Ros...
September 18, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/28921565/the-impact-of-p-glycoprotein-and-breast-cancer-resistance-protein-on-the-brain-pharmacokinetics-and-pharmacodynamics-of-a-panel-of-mek-inhibitors
#11
Mark C de Gooijer, Ping Zhang, Ruud Weijer, Levi C M Buil, Jos H Beijnen, Olaf van Tellingen
Mitogen/extracellular signal-regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood-brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP-dependent efflux transport proteins, of which P-gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain...
September 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28919996/mek-inhibition-and-immune-responses-in-advanced-melanoma
#12
REVIEW
Reinhard Dummer, Egle Ramelyte, Sabrina Schindler, Olaf Thürigen, Mitchell P Levesque, Peter Koelblinger
phase II and III clinical trials demonstrated modest anti- tumor activity of Binimetinib (MEK162) - a potent allosteric inhibitor of MEK1 and MEK2- in patients with advanced NRAS mutant melanoma. The analysis of the NEMO study in NRAS mutated melanoma, has shown that pre-treatment with immunotherapy improved the outcome of binimetinib therapy. We discuss this finding in the context of in vitro and in vivo effects of MEK inhibition on immuno-critical pathways and interactions.
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28918684/differential-induction-of-c-fos-and-phosphorylated-erk-by-a-noxious-stimulus-after-peripheral-nerve-injury
#13
Mitsuyasu Tabata, Ryuji Terayama, Kotaro Maruhama, Seiji Iida, Tomosada Sugimoto
Induction of c-Fos and phosphorylated extracellular signal-regulated kinase (p-ERK) has been demonstrated in spinal dorsal horn neurons by noxious stimuli. In this study, we compared induction of c-Fos and p-ERK in the spinal dorsal horn after peripheral nerve injury. We examined the spinal dorsal horn for noxious heat-induced c-Fos and p-ERK protein-like immunoreactive (c-Fos- and p-ERK-IR) neuron profiles after tibial nerve injury. A large number of c-Fos- and p-ERK-IR neuron profiles were induced by noxious heat stimulation to the hindpaw in sham-operated animals...
September 18, 2017: International Journal of Neuroscience
https://www.readbyqxmd.com/read/28918496/recurrent-papillary-craniopharyngioma-with-brafv600e-mutation-treated-with-neoadjuvant-targeted-therapy
#14
Elham Rostami, Petra Witt Nyström, Sylwia Libard, Johan Wikström, Olivera Casar-Borota, Olafur Gudjonsson
Craniopharyngiomas are histologically benign but locally aggressive tumors in the sellar region that may cause devastating neurological and endocrine deficits. They tend to recur following surgery with high morbidity; hence, postoperative radiotherapy is recommended following sub-total resection. BRAFV600E mutation is the principal oncogenic driver in the papillary variant of craniopharyngiomas. Recently, a dramatic tumor reduction has been reported in a patient with BRAFV600E mutated, multiply recurrent papillary craniopharyngioma using a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib...
September 16, 2017: Acta Neurochirurgica
https://www.readbyqxmd.com/read/28915798/vemurafenib-plus-cobimetinib-in-unresectable-stage-iiic-or-stage-iv-melanoma-response-monitoring-and-resistance-prediction-with-positron-emission-tomography-and-tumor-characteristics-reposit-study-protocol-of-a-phase-ii-open-label-multicenter-study
#15
Bernies van der Hiel, John B A G Haanen, Marcel P M Stokkel, Daniel S Peeper, Connie R Jimenez, Jos H Beijnen, Bart A van de Wiel, Ronald Boellaard, Alfons J M van den Eertwegh
BACKGROUND: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with (18)F-Fluorodeoxyglucose ((18)F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of (18)F-FDG uptake within 2 weeks following treatment...
September 15, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28915658/oxidative-stress-mediates-an-increased-formation-of-vascular-endothelial-growth-factor-in-human-hepatocarcinoma-cells-exposed-to-erlotinib
#16
Nataliya Rohr-Udilova, Florian Klinglmüller, Martha Seif, Hubert Hayden, Martin Bilban, Matthias Pinter, Klaus Stolze, Wolfgang Sieghart, Markus Peck-Radosavljevic, Michael Trauner
The tyrosine kinase inhibitor erlotinib targets the receptor of epidermal growth factor (EGFR) involved in development of hepatocellular carcinoma (HCC). Although inefficient in established HCC, erlotinib has been recently proposed for HCC chemoprevention. Since Cyp3A4 and Cyp1A2 enzymes metabolize erlotinib in the liver, the insights into the mechanisms of erlotinib effects on liver cells with maintained drug metabolizing activity are needed. We applied erlotinib to both commercially available (SNU398, Huh7) and established in Austria HCC cell lines (HCC-1...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28915644/phytoagent-deoxyelephantopin-derivative-inhibits-triple-negative-breast-cancer-cell-activity-by-inducing-oxidative-stress-mediated-paraptosis-like-cell-death
#17
Jeng-Yuan Shiau, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Lie-Fen Shyur
Triple negative breast cancer (TNBC) is a highly metastatic cancer among the breast cancer subgroups. A thorny issue for clinical therapy of TNBC is lack of an efficient targeted therapeutic strategy. We previously created a novel sesquiterpene lactone analog (named DETD-35) derived from plant deoxyelephantopin (DET) which exhibits potent effects against human TNBC MDA-MB-231 tumor growth in a xenograft mouse model. Here we studied the mechanisms of both DET and DETD-35 against MDA-MB-231 cells. DETD-35 (3-fold decreased in IC50) exhibited better anti-TNBC cell activity than DET as observed through induction of reactive oxygen species production (within 2 h treatment) and damage to the ER structures, resulting in ER-derived cytoplasmic vacuolation and ubiquitinated protein accumulation in the treated cells...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28915623/inhibition-of-the-pi3k-akt-mtor-pathway-activates-autophagy-and-compensatory-ras-raf-mek-erk-signalling-in-prostate-cancer
#18
Dominika E Butler, Christopher Marlein, Hannah F Walker, Fiona M Frame, Vincent M Mann, Matthew S Simms, Barry R Davies, Anne T Collins, Norman J Maitland
The PI3K/AKT/mTOR pathway is frequently activated in advanced prostate cancer, due to loss of the tumour suppressor PTEN, and is an important axis for drug development. We have assessed the molecular and functional consequences of pathway blockade by inhibiting AKT and mTOR kinases either in combination or as individual drug treatments. In established prostate cancer cell lines, a decrease in cell viability and in phospho-biomarker expression was observed. Although apoptosis was not induced, a G1 growth arrest was observed in PTEN null LNCaP cells, but not in BPH1 or PC3 cells...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28914804/the-role-of-erk-signaling-in-experimental-autoimmune-encephalomyelitis
#19
Katharina Birkner, Beatrice Wasser, Julia Loos, Alexander Plotnikov, Rony Seger, Frauke Zipp, Esther Witsch, Stefan Bittner
Extracellular signal-regulated kinase (ERK) signaling plays a crucial role in regulating immune cell function and has been implicated in autoimmune disorders. To date, all commercially available inhibitors of ERK target upstream components, such as mitogen-activated protein (MAP) kinase/ERK kinase (MEKs), but not ERK itself. Here, we directly inhibit nuclear ERK translocation by a novel pharmacological approach (Glu-Pro-Glu (EPE) peptide), leading to an increase in cytosolic ERK phosphorylation during T helper (Th)17 cell differentiation...
September 15, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28914644/systemic-therapy-in-advanced-melanoma-integrating-targeted-therapy-and-immunotherapy-into-clinical-practice
#20
Inês P Silva, Georgina V Long
PURPOSE OF REVIEW: Here we review the results from relevant phase III trials and discuss treatment strategies for challenging subgroups of melanoma patients. RECENT FINDINGS: Targeted therapies induce rapid responses in the majority of BRAF-mutant patients, however, 50% of these responders will develop resistance within approximately 13 months. In contrast, inhibitors of checkpoints on T cells, particularly inhibitors of PD-1, induce responses in 40-55% of patients (monotherapy or whenever combined with anti-CTLA-4), and these responses tend to be durable...
September 12, 2017: Current Opinion in Oncology
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