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https://www.readbyqxmd.com/read/28944867/succinate-promotes-skeletal-muscle-protein-synthesis-via-erk1-2-signaling-pathway
#1
Yexian Yuan, Yaqiong Xu, Jingren Xu, Bingqing Liang, Xingcai Cai, Canjun Zhu, Lina Wang, Songbo Wang, Xiaotong Zhu, Ping Gao, Xiuqi Wang, Yongliang Zhang, Qingyan Jiang, Gang Shu
It is well known that endurance training is effective to attenuate skeletal muscle atrophy. Succinate is a typical TCA metabolite, of which exercise could dramatically increase the content. The present study aimed to investigate the effect of succinate on protein synthesis in skeletal muscle, and try to delineate the underlying mechanism. The in vitro study revealed that succinate dose‑dependently increased protein synthesis in C2C12 myotube along with the enhancement of phosphorylation levels of AKT Serine/Threonine Kinase 1(Akt), mammalian target of rapamycin, S6, eukaryotic translation initiation factor 4E, 4E binding protein 1 and forkhead box O (FoxO) 3a...
September 20, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28944847/geniposide-promotes-autophagy-to-inhibit-insulin-resistance-in-hepg2-cells-via-p62-nf%C3%A2-%C3%AE%C2%BAb-glut%C3%A2-4
#2
Hongwei Jiang, Yujin Ma, Junqiang Yan, Jie Liu, Liping Li
Insulin resistance (IR) is known to be an important factor, which can lead to the onset of type 2 diabetes. Autophagy is a cellular process, which sequesters senescent or damaged proteins in autophagosomes for recycling of their products. Insulin and intracellular molecules, including mammalian target of rapamycin (mTOR), are well‑known inhibitors of autophagy. In patients with type 2 diabetes, the expression levels of glucose transporter 4 (GLUT‑4) in skeletal muscles are significantly decreased, indicating decreased glucose‑processing ability...
September 18, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28943602/deltamethrin-increases-neurite-outgrowth-in-cortical-neurons-through-endogenous-bdnf-trkb-pathways
#3
Daisuke Ihara, Mamoru Fukuchi, Momoko Katakai, Yo Shinoda, Ritsuko Katoh-Semba, Teiichi Furuichi, Mitsuru Ishikawa, Akiko Tabuchi, Masaaki Tsuda
Deltamethrin (DM), a type II pyrethroid, robustly increases brain-derived neurotrophic factor (Bdnf) expression and has a neurotrophic effect in primary cultures of rat cortical neurons. In this study, we investigated the effect of DM on neurite morphology in cultured rat cortical neurons. DM significantly increased neurite outgrowth, but this increase was abolished when the BDNF scavenger tropomyosin receptor kinase B (TrkB)-Fc was added 10 min before the DM treatment. In contrast, the addition of TrkB-Fc 1 h after the treatment did not affect DM-induced neurite outgrowth...
September 23, 2017: Cell Structure and Function
https://www.readbyqxmd.com/read/28941151/recurrent-desmoplastic-small-round-cell-tumor-responding-to-an-mtor-inhibitor-containing-regimen
#4
Nidale Tarek, Andrea Hayes-Jordan, Laura Salvador, Mary F McAleer, Cynthia E Herzog, Winston W Huh
Desmoplastic small round cell tumor (DSRCT) is a rare mesenchymal tumor that typically presents with multiple abdominal masses. Initial treatment is multimodal in nature. Patients with relapsed DSRCT have a poor prognosis, and there are no standard therapies. We report our experience with five patients treated with vinorelbine, cyclophosphamide, and temsirolimus (VCT). Median number of VCT courses delivered was 7 (range 4-14 courses), and partial response was observed in all patients. Median time to progression or relapse was 8...
September 22, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28939765/thioredoxin-1-maintains-mtor-function-during-oxidative-stress-in-cardiomyocytes
#5
Shin-Ichi Oka, Tsuyoshi Hirata, Wataru Suzuki, Daichi Naito, Yanbin Chen, Adave Chin, Hiroaki Yaginuma, Toshiro Saito, Narayani Nagarajan, Peiyong Zhai, Santosh Bhat, Kevin Schesing, Dan Shao, Yoko Hirabayashi, Junji Yodoi, Sebastiano Sciarretta, Junichi Sadoshima
Thioredoxin 1 (Trx1) is a 12 kDa oxidoreductase that catalyzes thiol-disulfide exchange reactions to reduce proteins with disulfide bonds. As such, Trx1 helps protect the heart against stresses, such as ischemia and pressure overload. Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth, metabolism and survival. We have previously shown that mTOR activity is increased in response to myocardial ischemia-reperfusion injury. However, whether Trx1 interacts with mTOR to preserve heart function remains unknown...
September 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28938574/the-dual-pi3k-mtor-inhibitor-gsk2126458-is-effective-for-treating-solid-renal-tumours-in-tsc2-mice-through-suppression-of-cell-proliferation-and-induction-of-apoptosis
#6
Kalin Narov, Jian Yang, Paulina Samsel, Ashley Jones, Julian R Sampson, Ming Hong Shen
Tuberous sclerosis (TSC) is an inherited tumour syndrome caused by mutations in TSC1 or TSC2 that lead to aberrant activation of mTOR. Tumour responses in TSC patients to rapamycin, an allosteric inhibitor of mTOR, or its analogs are partial and reversible probably due to feedback activation of Akt. In this study, we examined the efficacy of GSK2126458, an ATP-competitive dual inhibitor of PI3K/mTOR, in comparison to rapamycin for treatment of renal tumours in genetically engineered Tsc2(+/-) mice. We found that both GSK2126458 and rapamycin caused significant reduction in number and size of solid renal tumours...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938571/preclinical-study-of-cc223-as-a-potential-anti-ovarian-cancer-agent
#7
Zhenzhen Jin, Huanfu Niu, Xuenan Wang, Lei Zhang, Qin Wang, Aijun Yang
Aberrant activation of mTOR contributes to ovarian cancer progression. CC223 is a novel and potent mTOR kinase inhibitor. The current study tested its activity against human ovarian cancer cells. We showed that CC223, at nM concentrations, inhibited survival and proliferation of established/primary human ovarian cancer cells. Further, significant apoptosis activation was observed in CC223-treated ovarian cancer cells. CC223 disrupted assembly of mTOR complex 1 (mTORC1) and mTORC2 in SKOV3 cells. Meanwhile, activation of mTORC1 and mTORC2 was almost completely blocked by CC223...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28932590/primary-pulmonary-malignant-fibrous-histiocytoma-case-report-and-literature-review
#8
Xiongfei Li, Renwang Liu, Tao Shi, Shangwen Dong, Fan Ren, Fan Yang, Dian Ren, Haiyang Fan, Sen Wei, Gang Chen, Jun Chen, Song Xu
Malignant fibrous histiocytoma (MFH) is an aggressive soft tissue sarcoma known to occur in various organs. Primary MFH arising in the lung is quite rare. Herein we report a case of a 61-year-old male with primary pulmonary MFH and explore the underlying molecular mechanisms by next-generation sequencing (NGS). Five gene mutations in TSC2, ARID1B, CDK8, KDM5C and CASP8 were detected, and the mTOR inhibitor might be an effective treatment for this patient. In addition, we reviewed the scientific literature of approximately 23 primary pulmonary MFH case reports since 1990 and summarized the clinical features and prognosis of this rare pulmonary malignant tumor...
August 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/28931653/combined-ox40l-and-mtor-blockade-controls-effector-t-cell-activation-while-preserving-treg-reconstitution-after-transplant
#9
Victor Tkachev, Scott N Furlan, Benjamin Watkins, Daniel J Hunt, Hengqi Betty Zheng, Angela Panoskaltsis-Mortari, Kayla Betz, Melanie Brown, John B Schell, Katie Zeleski, Alison Yu, Ian Kirby, Sarah Cooley, Jeffrey S Miller, Bruce R Blazar, Duncan Casson, Phil Bland-Ward, Leslie S Kean
A critical question facing the field of transplantation is how to control effector T cell (Teff) activation while preserving regulatory T cell (Treg) function. Standard calcineurin inhibitor-based strategies can partially control Teffs, but breakthrough activation still occurs, and these agents are antagonistic to Treg function. Conversely, mechanistic target of rapamycin (mTOR) inhibition with sirolimus is more Treg-compatible but is inadequate to fully control Teff activation. In contrast, blockade of OX40L signaling has the capacity to partially control Teff activation despite maintaining Treg function...
September 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28928860/the-impact-of-cetuximab-plus-akt-or-mtor-inhibitor-in-a-patient-derived-colon-cancer-cell-model-with-wild-type-ras-and-pik3ca-mutation
#10
Ju Sun Kim, Jung Eun Kim, Kyung Kim, Jeeyun Lee, Joon Oh Park, Ho Yeong Lim, Young Suk Park, Won Ki Kang, Seung Tae Kim
Background: Anti-EGFR therapies have been recommended for advanced colorectal cancer (CRC) with wild-type RAS and PIK3CA mutation. However, PIK3CA mutations are a poor prognostic marker and a negative predictor of response to anti-EGFR therapies in RAS wild-type CRC. Therefore, new and advanced treatment strategies are needed for personalized medical treatment of patients with wild-type RAS and PIK3CA mutation. Methods: Patient-derived tumor cells were collected from the ascites of a refractory colon cancer patient with wild-type RAS and PIK3CA mutation...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28928817/dichloroacetate-induces-protective-autophagy-in-esophageal-squamous-carcinoma-cells
#11
Hong-Yu Jia, He-Nan Wang, Feng-Yu Xia, Yan Sun, Hong-Li Liu, Li-Li Yan, Shan-Shan Li, Dong-Chun Jiang, Mei-Mei Xu
Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase, which promotes the flux of carbohydrates into mitochondria and enhances the aerobic oxidation of glucose. DCA has previously been demonstrated to exhibit antitumor properties. The present study revealed that treatment with DCA induced increased levels of autophagy-associated proteins in esophageal squamous carcinoma cells while minimally affecting apoptosis. The present study examined the localization of light chain (LC)-3 by adenovirus infection with a green fluorescent protein (FP)-red FP-LC3 reporter construction and confirmed that DCA treatment induced significant autophagy...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28928082/mir-338-3p-confers-5-fluorouracil-resistance-in-p53-mutant-colon-cancer-cells-by-targeting-the-mammalian-target-of-rapamycin
#12
Jia Han, Jie Li, Kaijie Tang, Huahua Zhang, Bo Guo, Ni Hou, Chen Huang
Evidence demonstrate that p53 mutations and microRNAs (miRs) are important components of 5-FU resistance in colorectal cancer (CRC). miR-338-3p has been reported associated with cancer prognosis. However whether or not it influences chemotherapy sensitivity and the underlying mechanisms have not been elucidated. Here, three types of human colon cancer cell lines, HT29 (mutant p53), HCT116 (wild-type p53), and HCT116 p53(-/-) (deficient p53), were treated with 5-FU. We showed that expression of miR-338-3p was correlated with apoptosis and 5-FU resistance in colon cancer cells...
September 18, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28927154/resistance-to-the-mtor-inhibitor-everolimus-is-reversed-by-the-downregulation-of-survivin-in-breast-cancer-cells
#13
Ludovica Taglieri, Francesca De Iuliis, Anna Giuffrida, Sabrina Giantulli, Ida Silvestri, Susanna Scarpa
Everolimus (RAD001) is an inhibitor of mammalian target of rapamycin used in combination with exemestane to treat hormone receptor-positive advanced breast cancer. However, not all patients are equally sensitive to RAD001 and certain patients develop resistance. Therefore, the present study analyzed the mechanisms involved in the resistance of breast cancer cells to RAD001 in order to identify a potential tool to overcome it. The effects of RAD001 on the inhibition of cell viability, on the induction of apoptosis and autophagy and on the regulation of survivin, an anti-apoptotic protein, were evaluated in two breast cancer cell lines: BT474 (luminal B) and MCF7 (luminal A)...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28927113/inhibition-of-autophagy-potentiates-the-proliferation-inhibition-activity-of-microrna-7-in-human-hepatocellular-carcinoma-cells
#14
Yanna Wang, Qiaoling Wang, Jiqing Song
MicroRNAs (miRNAs/miRs) are important molecules that are able to regulate multiple cellular processes in cancer cells. miR-7 has been previously identified as a tumor suppressive miRNA in several types of cancer. The aim of the present study was to investigate whether miR-7 is able to regulate autophagy in hepatocellular carcinoma (HCC) cells. It was identified that miR-7 was significantly downregulated in tumor tissues compared with adjacent normal tissues. Overexpression of miR-7 inhibited cell proliferative activity, which was partially reversed by miR-7 inhibitor...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28927111/luteolin-reduces-migration-of-human-glioblastoma-cell-lines-via-inhibition-of-the-p-igf-1r-pi3k-akt-mtor-signaling-pathway
#15
Qiang Wang, Handong Wang, Yue Jia, Hui Ding, Li Zhang, Hao Pan
Luteolin (3',4',5,7-tetrahydroxyflavone) is a common dietary flavonoid, which has been demonstrated to exert anticancer effects in multiple cancer models. However, the detailed mechanisms underlying the inhibitory effect of luteolin on glioblastoma cell metastasis remain poorly understood. The present study assessed the effects of luteolin in the U251MG and U87MG human glioblastoma cell lines. Luteolin treatment significantly inhibited glioblastoma cell migration, and this effect was associated with downregulated matrix metalloproteinase (MMP)-2, MMP-9 and upregulated tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28927052/synergistic-effects-of-phenylhexyl-isothiocyanate-and-ly294002-on-the-pi3k-akt-signaling-pathway-in-hl-60-cells
#16
Huicong Yang, Yiqun Huang, Yong Zou, Xudong Ma
The aim of the present study was to investigate the synergistic effect of phenylhexyl isothiocyanate (PHI) and LY294002 [an inhibitor of phosphoinositide 3-kinase (PI3K)] on the PI3K/protein kinase B (Akt) signaling pathway, modulating histone acetylation, inhibiting cell viability and inducing apoptosis in HL-60 cells. The inhibition of HL-60 cell viability was monitored using an MTT assay. Cell apoptosis was measured using flow cytometry. Expression of acetylated histone H3 and histone H4, and the Akt signaling pathway proteins phosphorylated Akt (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR) and phosphorylated ribosomal protein S6 kinase (p-p70S6K) was detected using western blotting...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28926616/co-ordinated-activation-of-classical-and-novel-pkc-isoforms-is-required-for-pma-induced-mtorc1-activation
#17
Mengling Liu, Christopher J Clarke, Mohamed F Salama, Yeon Ja Choi, Lina M Obeid, Yusuf A Hannun
Protein kinase C (PKC) has been shown to activate the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, a central hub in the regulation of cell metabolism, growth and proliferation. However, the mechanisms by which PKCs activate mTORC1 are still ambiguous. Our previous study revealed that activation of classical PKCs (cPKC) results in the perinuclear accumulation of cPKC and phospholipase D2 (PLD2) in recycling endosomes in a PLD2-dependent manner. Here, we report that mTORC1 activation by phorbol 12,13-myristate acetate (PMA) requires both classic, cPKC, and novel PKC (nPKC) isoforms, specifically PKCη, acting through distinct pathways...
2017: PloS One
https://www.readbyqxmd.com/read/28926611/activation-of-the-unfolded-protein-response-in-sarcoma-cells-treated-with-rapamycin-or-temsirolimus
#18
Joseph W Briggs, Ling Ren, Kristi R Chakrabarti, Yien Che Tsai, Allan M Weissman, Ryan J Hansen, Daniel L Gustafson, Yousuf A Khan, Jonathan D Dinman, Chand Khanna
Activation of the unfolded protein response (UPR) in eukaryotic cells represents an evolutionarily conserved response to physiological stress. Here, we report that the mTOR inhibitors rapamycin (sirolimus) and structurally related temsirolimus are capable of inducing UPR in sarcoma cells. However, this effect appears to be distinct from the classical role for these drugs as mTOR inhibitors. Instead, we detected these compounds to be associated with ribosomes isolated from treated cells. Specifically, temsirolimus treatment resulted in protection from chemical modification of several rRNA residues previously shown to bind rapamycin in prokaryotic cells...
2017: PloS One
https://www.readbyqxmd.com/read/28923937/direct-engagement-of-the-pi3k-pathway-by-mutant-kit-dominates-oncogenic-signaling-in-gastrointestinal-stromal-tumor
#19
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/28923401/pharmacological-blockade-of-cholesterol-trafficking-by-cepharanthine-in-endothelial-cells-suppresses-angiogenesis-and-tumor-growth
#20
Junfang Lyu, Eun Ju Yang, Sarah A Head, Nana Ai, Baoyuan Zhang, Changjie Wu, Ruo-Jing Li, Yifan Liu, Chen Yang, Yongjun Dang, Ho Jeong Kwon, Wei Ge, Jun O Liu, Joong Sup Shim
Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis...
September 18, 2017: Cancer Letters
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