Search results for "mTOR"
showing 10 items of 275 documents
New agents and approaches for targeting the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell survival pathways.
2012
The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Targeting these pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type (WT) RAF in the presence of mutant, activated RAS) and rapamycin can induce Akt activation. Targeting with inhibitors directed at two constituents of the same pathway or two different signaling pathways may be a more effective approach. This review will first evaluate potential uses of Raf, MEK, PI3K, Akt and mTOR inhibitors that have…
Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies
2020
AbstractThere are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of …
Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: Rationale and importance to inhibiting these pathways in human health
2011
William H. Chappell 1 , Linda S. Steelman 1,2 , Jacquelyn M. Long 2 , Ruth C. Kempf 2 , Stephen L. Abrams 1 , Richard A. Franklin 1 , Jorg Basecke 3 , Franca Stivala 4 , Marco Donia 4 , Paolo Fagone 4 , Graziella Malaponte 4 , Maria C. Mazzarino 4 , Ferdinando Nicoletti 4 , Massimo Libra 4 , Danijela Maksimovic-Ivanic 5 , Sanja Mijatovic 5 , Giuseppe Montalto 6 , Melchiorre Cervello 7 , Piotr Laidler 8 , Michele Milella 9 , Agostino Tafuri 10 , Antonio Bonati 11 , Camilla Evangelisti 12 , Lucio Cocco 12 , Alberto M. Martelli 12,13 , and James A. McCubrey 1 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University 2 Department of Physics, Greenville, N…
Cajaninstilbene acid (CSA) exerts cytoprotective effects against oxidative stress through the Nrf2-dependent antioxidant pathway.
2013
Cajaninstilbene acid (CSA), an active compound separated from pigeon pea leaves, possesses the highly efficient antioxidant activities. Transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important regulator of cellular oxidative stress. This study examined the role of Nrf2 in CSA-mediated antioxidant effects on human hepatocarcinoma (HepG2) cell line. The generation of reactive oxygen species (ROS) upon H2O2 and CSA treatment was lower than that of H2O2 alone. CSA activated Nrf2 as evaluated by Western blotting. A luciferase reporter assay also demonstrated that CSA-activated signaling resulted in the increased transcriptional activity of Nrf2 through binding to t…
Evaluation and clinical analyses of downstream targets of the Akt inhibitor GDC-0068.
2013
Abstract Purpose: The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3 inhibitor, in preclinical models and in patients treated with this compound. Experimental Design: We used a reverse phase protein array (RPPA) platform to identify a biomarker set indicative of Akt inhibition in cell lines and human-tumor xenografts, and correlated the degree of pathway inhibition with antitumor activity. Akt pathway activity was measured using this biomarker se…
Multifaceted roles of GSK-3 and Wnt/beta-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention
2013
Glycogen synthase kinase-3 (GSK-3) is well documented to participate in a complex array of critical cellular processes. It was initially identified in rat skeletal muscle as a serine/threonine kinase that phosphorylated and inactivated glycogen synthase. This versatile protein is involved in numerous signaling pathways that influence metabolism, embryogenesis, differentiation, migration, cell cycle progression and survival. Recently, GSK-3 has been implicated in leukemia stem cell pathophysiology and may be an appropriate target for its eradication. In this review, we will discuss the roles that GSK-3 plays in hematopoiesis and leukemogenesis as how this pivotal kinase can interact with mul…
Three-dimensional invasion of human glioblastoma cells remains unchanged by X-ray and carbon ion irradiation in vitro.
2012
Purpose Cell invasion represents one of the major determinants that treatment has failed for patients suffering from glioblastoma. Contrary findings have been reported for cell migration upon exposure to ionizing radiation. Here, the migration and invasion capability of glioblastoma cells on and in collagen type I were evaluated upon irradiation with X-rays or carbon ions. Methods and Materials Migration on and invasion in collagen type I were evaluated in four established human glioblastoma cell lines exposed to either X-rays or carbon ions. Furthermore, clonogenic radiation survival, proliferation (5-bromo-2-deoxyuridine positivity), DNA double-strand breaks (γH2AX/53BP1-positive foci), a…
The novel dual PI3K/mTOR inhibitor GDC-0941 synergizes with the MEK inhibitor U0126 in non-small cell lung cancer cells.
2011
Lung cancer is a malignant disease with poor outcome, which has led to a search for new therapeutics. The PI3K/Akt/mTOR and Ras/raf/Erk pathways are key regulators of tumor growth and survival. In the present study, their roles were evaluated by MTT assay, flow cytometry and Western blotting in lung cancer cells. We found that a high efficacy of antitumor activity was shown with GDC-0941 treatment in two gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines, A549 and H460. In addition, H460 cells with activating mutations of PIK3CA were relatively more sensitive to GDC-0941 than A549 cells with wild-type PIK3CA. Furthermore, GDC-0941 was highly efficacious in combination with U0…
Roles of EGFR and KRAS and their downstream signaling pathways in pancreatic cancer and pancreatic cancer stem cells
2015
Pancreatic cancer is currently the fourth most common cancer, is increasing in incidence and soon will be the second leading cause of cancer death in the USA. This is a deadly malignancy with an incidence that approximates the mortality with 44,000 new cases and 36,000 deaths each year. Surgery, although only modestly successful, is the only curative option. However, due the locally aggressive nature and early metastasis, surgery can be performed on less than 20% of patients. Cytotoxic chemotherapy is palliative, has significant toxicity and improves survival very little. Thus new treatment paradigms are needed desperately. Due to the extremely high frequency of KRAS gene mutations (>90%) d…
Activity-dependent survival of developing neocortical neurons depends on PI3K signalling
2011
J. Neurochem. (2012) 120, 495–501. Abstract Spontaneous electrical network activity plays a major role in the control of cell survival in the developing brain. Several intracellular pathways are implicated in transducing electrical activity into gene expression dependent and independent survival signals. These include activation of phosphatidylinositol 3-kinase (PI3K) and its downstream effector Akt, activation of Ras and subsequently MAPK/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase and signalling via calcium/calmodulin-dependent protein kinase (CaMK). In the present study, we analyzed the role of these pathways for the control of neuronal survival …