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https://www.readbyqxmd.com/read/29777434/ascorbic-acid-inhibits-senescence-in-mesenchymal-stem-cells-through-ros-and-akt-mtor-signaling
#1
Mengkai Yang, Songsong Teng, Chunhui Ma, Yinxian Yu, Peilin Wang, Chengqing Yi
Mesenchymal stem cell (MSC) aging seriously affects its function in stem cell transplantation for treatment. Extensive studies have focused on how to inhibit senescence in MSCs. However, the mechanism of senescence in MSC was not clear. In this study, we used D-galactose to induce MSC aging. Then we found that the number of aging cells was increased compared with untreated MSCs. We discovered that ascorbic acid could inhibit the production of reactive oxygen species (ROS) and activation of AKT/mTOR signaling in MSCs caused by D-galactose...
May 18, 2018: Cytotechnology
https://www.readbyqxmd.com/read/29777330/down-regulating-il-6-gp130-targets-improved-the-anti-tumor-effects-of-5-fluorouracil-in-colon-cancer
#2
Sanhong Li, Jilai Tian, Hongming Zhang, Shoubing Zhou, Xiyong Wang, Lei Zhang, Jiapeng Yang, Zhigang Zhang, Zhenling Ji
Recent studies have confirmed that IL-6/GP130 targets are closely associated with tumor growth, metastasis and drug resistance. 5-Fluorouracil (5-FU) is the most common chemotherapeutic agent for colon cancer but is limited due to chemoresistance and high cytotoxicity. Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator, was discovered by multiple ligand simultaneous docking and drug repositioning approaches to have a novel function as an IL-6/GP130 target inhibitor. Thus, we speculated that in colon cancer, the anti-tumor efficacy of 5-FU might be increased in combination with IL-6/GP130 inhibitors...
May 18, 2018: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/29777202/aberrant-modulation-of-ribosomal-protein-s6-phosphorylation-confers-acquired-resistance-to-mapk-pathway-inhibitors-in-braf-mutant-melanoma
#3
Ming-Zhao Gao, Hong-Bin Wang, Xiang-Ling Chen, Wen-Ting Cao, Li Fu, Yun Li, Hai-Tian Quan, Cheng-Ying Xie, Li-Guang Lou
BRAF and MEK inhibitors have shown remarkable clinical efficacy in BRAF-mutant melanoma; however, most patients develop resistance, which limits the clinical benefit of these agents. In this study, we found that the human melanoma cell clones, A375-DR and A375-TR, with acquired resistance to BRAF inhibitor dabrafenib and MEK inhibitor trametinib, were cross resistant to other MAPK pathway inhibitors. In these resistant cells, phosphorylation of ribosomal protein S6 (rpS6) but not phosphorylation of ERK or p90 ribosomal S6 kinase (RSK) were unable to be inhibited by MAPK pathway inhibitors...
May 18, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29777201/novel-smoothened-inhibitors-for-therapeutic-targeting-of-na%C3%A3-ve-and-drug-resistant-hedgehog-pathway-driven-cancers
#4
Qing-Rou Li, Hui Zhao, Xue-Sai Zhang, Henk Lang, Ker Yu
The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. The FDA-approved SMO inhibitors GDC-0449/Vismodegib and LDE225/Sonidegib demonstrated clinical antitumor efficacy. Nevertheless, relatively high percentage of treated patients would eventually develop acquired cross resistance to both drugs. Here, based on published structure and activity of GDC-0449 inhibitor class, we replaced its amide core with benzimidazole which retained bulk of the SMO-targeting activity as measured in our Hh/SMO/Gli1-reporter system...
May 18, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29776912/targeting-glutaminase-may-overcome-resistance-to-mtor-inhibition
#5
(no author information available yet)
mTOR inhibitor-mediated suppression of glycolysis results in a compensatory increase in glutaminolysis.
May 18, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29774105/pre-clinical-activity-of-targeting-the-pi3k-akt-mtor-pathway-in-burkitt-lymphoma
#6
Maria Bhatti, Thomas Ippolito, Cory Mavis, Juan Gu, Mitchell S Cairo, Megan S Lim, Francisco Hernandez-Ilizaliturri, Matthew J Barth
Though outcomes for pediatric Burkitt lymphoma (BL) have improved significantly in recent decades with intensive multi-agent chemotherapy and the addition of rituximab, chemotherapy resistance remains a significant impediment to cure following relapse. Activation of the PI3K/AKT pathway has been implicated in Burkitt lymphomagenesis and increased PI3K/AKT activation has been associated with worse outcomes in adults with aggressive B-cell non-Hodgkin lymphoma (B-NHL). Inhibitors of the PI3K/AKT pathway have been approved for the treatment of refractory indolent B-NHL and continue to be investigated for treatment of aggressive B-NHLs...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29773990/atorvastatin-inhibits-inflammatory-response-attenuates-lipid-deposition-and-improves-the-stability-of-vulnerable-atherosclerotic-plaques-by-modulating-autophagy
#7
Shi Peng, Long-Wei Xu, Xin-Yu Che, Qing-Qing Xiao, Jun Pu, Qin Shao, Ben He
Atherosclerosis is a chronic disease comprising intima malfunction and arterial inflammation. Recent studies have demonstrated that autophagy could inhibit inflammatory response in atherosclerosis and exert subsequent atheroprotective effects. Our previous study also demonstrated the role of autophagy in the inhibition of inflammation by atorvastatin in vitro . Therefore, in the present study, we aimed to determine whether atorvastatin could upregulate autophagy to inhibit inflammatory cytokines secretion, lipid accumulation, and improve vulnerable plaque stability, both in vitro and in vivo ...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29772587/anti-inflammatory-effects-of-cardamonin-in-ovarian-cancer-cells-are-mediated-via-mtor-suppression
#8
Huajiao Chen, Daohua Shi, Peiguang Niu, Yanting Zhu, Jintuo Zhou
Cardamonin exhibits a variety of pharmacological activities including anti-inflammatory and antitumor, which are correlated with the inhibition of nuclear factor-kappaB and the mammalian target of rapamycin, respectively. However, whether the anti-inflammatory effects of cardamonin are mediated by the mammalian target of rapamycin remains unknown. In this study, ovarian cancer SKOV3 cells were cultured with lipopolysaccharide to induce inflammation, and the inhibitory effects and underlying molecular mechanisms of cardamonin were investigated using specific inhibitors of the mammalian target of rapamycin and the nuclear factor-kappaB pathway (rapamycin and pyrrolidine dithiocarbamate, respectively)...
May 17, 2018: Planta Medica
https://www.readbyqxmd.com/read/29770446/anticancer-activity-of-tetrandrine-by-inducing-pro-death-apoptosis-and-autophagy-in-human-gastric-cancer-cells
#9
Xin-Yu Bai, Yuan-Gui Liu, Wu Song, Ying-Ying Li, Dong-Shun Hou, Hao-Ming Luo, Ping Liu
OBJECTIVES: To investigate the antitumour property of tetrandrine by inducing autophagy and apoptosis in human gastric cancer cells, and to explore the potential molecular mechanisms. METHODS: The antitumour activity of tetrandrine was assessed through MTT assay. Apoptosis was measured by flow cytometry and microscopic examination of cellular morphology. The mitochondrial membrane potential was detected by staining with Rh-123. Induction of autophagy was monitored by transmission electron microscopy observation, using GFP-LC3 transfection...
May 16, 2018: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/29769264/rhoa-g17v-is-sufficient-to-induce-autoimmunity-and-promotes-t-cell-lymphomagenesis-in-mice
#10
Samuel Y Ng, Leon Brown, Kristen Stevenson, Tiffany deSouza, Jon C Aster, Abner Louissaint, David M Weinstock
Patients with angioimmunoblastic T-cell lymphoma (AITL) and other peripheral T-cell lymphomas (PTCL) that harbor features of follicular helper T (TFH) cells have a very poor prognosis. These lymphomas commonly present with paraneoplastic autoimmunity and lymphopenia. RhoA G17V mutation is present in 60% of TFH-like lymphomas but its role in tumorigenesis is poorly understood. We generated transgenic mice that express RhoA G17V under the control of murine CD4 regulatory elements at levels comparable to a heterozygous mutation (tgRhoA mice)...
May 16, 2018: Blood
https://www.readbyqxmd.com/read/29768192/nuclear-export-inhibition-enhances-hlh-30-tfeb-activity-autophagy-and-lifespan
#11
Melissa J Silvestrini, Joseph R Johnson, Anita V Kumar, Tara G Thakurta, Karine Blais, Zachary A Neill, Sarah W Marion, Victoria St Amand, Robert A Reenan, Louis R Lapierre
Transcriptional modulation of the process of autophagy involves the transcription factor HLH-30/TFEB. In order to systematically determine the regulatory network of HLH-30/TFEB, we performed a genome-wide RNAi screen in C. elegans and found that silencing the nuclear export protein XPO-1/XPO1 enhances autophagy by significantly enriching HLH-30 in the nucleus, which is accompanied by proteostatic benefits and improved longevity. Lifespan extension via xpo-1 silencing requires HLH-30 and autophagy, overlapping mechanistically with several established longevity models...
May 15, 2018: Cell Reports
https://www.readbyqxmd.com/read/29765774/how-shall-we-treat-early-triple-negative-breast-cancer-tnbc-from-the-current-standard-to-upcoming-immuno-molecular-strategies
#12
REVIEW
Ji Hyun Park, Jin-Hee Ahn, Sung-Bae Kim
Triple-negative breast cancer (TNBC) is a long-lasting orphan disease in terms of little therapeutic progress during the past several decades and still the standard of care remains chemotherapy. Experimental discovery of molecular signatures including the 'BRCAness' highlighted the innate heterogeneity of TNBC, generating the diversity of TNBC phenotypes. As it contributes to enhancing genomic instability, it has widened the therapeutic spectrum of TNBC. In particular, unusual sensitivity to DNA damaging agents was denoted in patients with BRCA deficiency, suggesting therapeutic benefit from platinum and poly(ADP-ribose) polymerase inhibitors...
2018: ESMO Open
https://www.readbyqxmd.com/read/29765553/acquired-resistance-to-everolimus-in-aromatase-inhibitor-resistant-breast-cancer
#13
Mariko Kimura, Toru Hanamura, Kouki Tsuboi, Yosuke Kaneko, Yuri Yamaguchi, Toshifumi Niwa, Kazutaka Narui, Itaru Endo, Shin-Ichi Hayashi
We previously reported the establishment of several types of long-term estrogen-depleted-resistant (EDR) cell lines from MCF-7 breast cancer cells. Type 1 EDR cells exhibited the best-studied mechanism of aromatase inhibitor (AI) resistance, in which estrogen receptor (ER) expression remained positive and PI3K signaling was upregulated. Type 2 EDR cells showed reduced ER activity and upregulated JNK-related signaling. The mTOR inhibitor everolimus reduced growth in cells similar to Type 1 EDR cells. The present study generated everolimus-resistant (EvR) cells from Types 1 and 2 EDR cells following long-term exposure to everolimus in vitro ...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29765528/metabolic-changes-associated-with-metformin-potentiates-bcl-2-inhibitor-venetoclax-and-cdk9-inhibitor-bay1143572-and-reduces-viability-of-lymphoma-cells
#14
Vineela Chukkapalli, Leo I Gordon, Parameswaran Venugopal, Jeffrey A Borgia, Reem Karmali
Metformin exerts direct anti-tumor effects by activating AMP-activated protein kinase (AMPK), a major sensor of cellular metabolism in cancer cells. This, in turn, inhibits pro-survival mTOR signaling. Metformin has also been shown to disrupt complex 1 of the mitochondrial electron transport chain. Here, we explored the lymphoma specific anti-tumor effects of metformin using Daudi (Burkitt), SUDHL-4 (germinal center diffuse large B-cell lymphoma; GC DLBCL), Jeko-1 (Mantle-cell lymphoma; MCL) and KPUM-UH1 (double hit DLBCL) cell lines...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29765318/utility-of-a-novel-three-dimensional-and-dynamic-3dd-cell-culture-system-for-pk-pd-studies-evaluation-of-a-triple-combination-therapy-at-overcoming-anti-her2-treatment-resistance-in-breast-cancer
#15
Anusha Ande, Tanaya R Vaidya, Bao N Tran, Michael Vicchiarelli, Ashley N Brown, Sihem Ait-Oudhia
Background: Emergence of Human epidermal growth factor receptor 2 (HER2) therapy resistance in HER2-positive (HER2+) breast cancer (BC) poses a major clinical challenge. Mechanisms of resistance include the over-activation of the PI3K/mTOR and Src pathways. This work aims to investigate a novel combination therapy that employs paclitaxel (PAC), a mitotic inhibitor, with everolimus (EVE), an mTOR inhibitor, and dasatinib (DAS), an Src kinase inhibitor, as a modality to overcome resistance. Methods: Static (two dimensional, 2D) and three-dimensional dynamic (3DD) cell culture studies were conducted using JIMT-1 cells, a HER2+ BC cell line refractory to HER2 therapies...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29765173/hemodiafiltration-and-plasma-levels-of-axitinib-in-a-patient-with-metastatic-renal-clear-cell-carcinoma
#16
Jindrich Kopecky, Alena Ticha, Hana Janeckova, Melichar Bohuslav
BACKGROUND: The standard treatment for metastatic renal cancer is based on vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTor) inhibitors. Compared to other advanced tumors, the treatment of renal cancer is highly affected by impaired renal function; therefore, patients with severe renal insufficiency, including patients on hemodialysis, are generally excluded from clinical trials. CASE REPORT: In the present manuscript we present the case of a renal cancer patient who underwent bilateral nephrectomy and received two lines of treatment...
May 15, 2018: Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia
https://www.readbyqxmd.com/read/29765155/genetic-transcriptional-and-post-translational-regulation-of-the-programmed-death-protein-ligand-1-in-cancer-biology-and-clinical-correlations
#17
REVIEW
Ioannis Zerdes, Alexios Matikas, Jonas Bergh, George Z Rassidakis, Theodoros Foukakis
The programmed death protein 1 (PD-1) and its ligand (PD-L1) represent a well-characterized immune checkpoint in cancer, effectively targeted by monoclonal antibodies that are approved for routine clinical use. The regulation of PD-L1 expression is complex, varies between different tumor types and occurs at the genetic, transcriptional and post-transcriptional levels. Copy number alterations of PD-L1 locus have been reported with varying frequency in several tumor types. At the transcriptional level, a number of transcriptional factors seem to regulate PD-L1 expression including HIF-1, STAT3, NF-κΒ, and AP-1...
May 16, 2018: Oncogene
https://www.readbyqxmd.com/read/29764404/advanced-sporadic-renal-epithelioid-angiomyolipoma-case-report-of-an-extraordinary-response-to-sirolimus-linked-to-tsc2-mutation
#18
Marta Espinosa, Juan Maria Roldán-Romero, Ignacio Duran, Enrique de Álava, María Apellaniz-Ruiz, Alberto Cascón, Carmen Garrigos, Mercedes Robledo, Cristina Rodriguez-Antona
BACKGROUND: Renal epithelioid angiomyolipomas (EAML) are rare tumors with aggressive behavior. EAML can be sporadic or develop within the tuberous sclerosis complex syndrome, where mutations of TSC1 or TSC2 genes (critical negative regulators of mTOR Complex 1) result in an increased activation of mTOR pathway. Optimal EAML treatment, including mTOR inhibitors, remains undetermined. CASE PRESENTATION: Here we present the case of a young adult with a renal EAML that after radical nephrectomy developed metastases, first in liver and then in lumbar vertebrae...
May 15, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29763685/autophagy-plays-a-pro-survival-role-against-methamphetamine-induced-apoptosis-in-h9c2-cells
#19
Chao Zhao, Yong Mei, Xufeng Chen, Lei Jiang, Yunfei Jiang, Xu Song, Hang Xiao, Jun Wang, Jingsong Zhang
Methamphetamine (METH) is a commonly abused psychostimulant that can induce severe neurotoxicity. Cardiovascular injury caused by METH has recently gained increasing attention; however, the underlying mechanisms remain unclear. As autophagy has been shown to be associated with cell injury, the association between autophagy and METH-mediated cell apoptosis was investigated in the present study. METH treatment significantly increased the expression of two key autophagy proteins, i.e., Beclin-1 and LC3-II, in the cardiomyocyte cell line H9C2...
May 12, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29763624/the-gsk3-signaling-axis-regulates-adaptive-glutamine-metabolism-in-lung-squamous-cell-carcinoma
#20
Milica Momcilovic, Sean T Bailey, Jason T Lee, Michael C Fishbein, Daniel Braas, James Go, Thomas G Graeber, Francesco Parlati, Susan Demo, Rui Li, Tonya C Walser, Michael Gricowski, Robert Shuman, Julio Ibarra, Deborah Fridman, Michael E Phelps, Karam Badran, Maie St John, Nicholas M Bernthal, Noah Federman, Jane Yanagawa, Steven M Dubinett, Saman Sadeghi, Heather R Christofk, David B Shackelford
Altered metabolism is a hallmark of cancer growth, forming the conceptual basis for development of metabolic therapies as cancer treatments. We performed in vivo metabolic profiling and molecular analysis of lung squamous cell carcinoma (SCC) to identify metabolic nodes for therapeutic targeting. Lung SCCs adapt to chronic mTOR inhibition and suppression of glycolysis through the GSK3α/β signaling pathway, which upregulates glutaminolysis. Phospho-GSK3α/β protein levels are predictive of response to single-therapy mTOR inhibition while combinatorial treatment with the glutaminase inhibitor CB-839 effectively overcomes therapy resistance...
May 14, 2018: Cancer Cell
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