Search results for "INHIBITORS"
showing 10 items of 2336 documents
Targeting the mevalonate pathway for improved anticancer therapy.
2009
The mevalonate pathway is important for the generation of isoprene moieties thereby providing the basis for the biosynthesis of molecules required for maintaining membrane integrity, steroid production and cell respiration. Additionally, isoprene precursors are indispensable for the prenylation of regulatory proteins such as Ras and Ras-homologous (Rho) GTPases. These low molecular GTP-binding proteins play key roles in numerous signal transduction pathways stimulated upon activation of cell surface receptors by ligand binding. Thus, Ras/Rho proteins eventually regulate cell proliferation, tumor progression and cell death induced by anticancer therapeutics. Lipid modification of Ras/Rho pro…
Inhibition of small G proteins of the Rho family by statins orClostridium difficiletoxin B enhances cytokine-mediated induction of NO synthase II
2000
In order to investigate the involvement of Ras and/or Rho proteins in the induction of the inducible isoform of nitric oxide synthase (NOS II) we used HMG-CoA reductase inhibitors (statins) and Clostridium difficile toxin B (TcdB) as pharmacological tools. Statins indirectly inhibit small G proteins by preventing their essential farnesylation (Ras) and/or geranylgeranylation (Rho). In contrast, TcdB is a glucosyltransferase and inactivates Rho-proteins directly. Human A549/8- and DLD-1 cells as well as murine 3T3 fibroblasts were preincubated for 18 h with statins (1–100 μM) or TcdB (0.01–10 ng ml−1). Then NOS II expression was induced by cytokines. NOS II mRNA was measured after 4–8 h by R…
Activation of astroglial phospholipase D activity by phorbol ester involves ARF and Rho proteins.
2000
Primary cultures of rat cortical astrocytes express phospholipase D (PLD) isoforms 1 and 2 as determined by RT-PCR and Western blot. Basal PLD activity was strongly (10-fold) increased by 4beta-phorbol-12beta,13alpha-dibutyrate (PDB) (EC(50): 56 nM), an effect which was inhibited by Ro 31-8220 (0.1-1 microM), an inhibitor of protein kinase C (PKC), and by brefeldin A (10-100 microg/ml), an inhibitor of ADP-ribosylating factor (ARF) activation. Pretreatment of the cultures with Clostridium difficile toxin B-10463 (0.1-1 ng/ml), which inactivates small G proteins of the Rho family, led to a breakdown of the astroglial cytoskeleton; concomitantly, PLD activation by PDB was reduced by up to 50%…
Metabotropic glutamate receptors activate phospholipase D in astrocytes through a protein kinase C-dependent and Rho-independent pathway.
2003
Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that mediate phospholipase D (PLD) activation in brain, but the mechanism underlying this response remains unclear. Here we used primary cultures of astrocytes as a cell model to explore the mechanism that links mGluRs to PLD. Glutamate activated both phospholipase C (PLC) and PLD with equal potency and this effect was mimicked by L-cysteinesulfinic acid, a putative neurotransmitter previously shown to activate mGluRs coupled to PLD, but not PLC, in adult brain. PLD activation by glutamate was dependent on Ca(2+) mobilization and fully blocked by both protein kinase C (PKC) inhibitors and PKC down-regulation, suggesti…
Rho GTPases: Promising Cellular Targets for Novel Anticancer Drugs
2006
Ras-homologous (Rho) GTPases play a pivotal role in the regulation of numerous cellular functions associated with malignant transformation and metastasis. Rho GTPases are localized at membranes and become activated upon stimulation of cell surface receptors. In their GTP-bound (=active) state, Rho proteins bind to effector proteins, thereby triggering specific cellular responses. Members of the Rho family of small GTPases are key regulators of actin reorganization, cell motility, cell-cell and cell-extracellular matrix (ECM) adhesion as well as of cell cycle progression, gene expression and apoptosis. Each of these functions is of importance for the development and progression of cancer. Fu…
Inhibition of Protein Isoprenylation Impairs Rho-Regulated Early Cellular Response to Genotoxic Stress
2000
Activation of c-Jun N-terminal kinases (JNKs) and nuclear factor-kappaB (NF-kappaB) are early cellular responses to genotoxic stress involved in the regulation of gene expression. Pretreatment of cells with the hydroxymethyl glutaryl-CoA reductase inhibitor lovastatin blocked stimulation of JNK1 activity by UV irradiation and by treatment with the alkylating compound methyl methanesulfonate but did not affect activation of extracellular signal-regulated kinase 2 by UV light. Lovastatin also attenuated UV-induced degradation of the NF-kappaB inhibitor IkappaBalpha. The effects of lovastatin on UV-triggered stimulation of JNK1 as well as on IkappaBalpha degradation were reverted by cotreatmen…
Safety of Tyrosine Kinase Inhibitors in Patients With Differentiated Thyroid Cancer: Real-World Use of Lenvatinib and Sorafenib in Korea
2019
Background: Thyroid cancer has become the most common cancer in Korea. Generally, thyroid cancer patients have a good prognosis; however, 15–20% of patients experience recurrence or distant metastasis or are refractory to standard treatment. We assessed the safety of sorafenib and lenvatinib in patients with advanced or metastatic radioactive iodine-refractory differentiated thyroid cancers (DTC) consecutively treated at a tertiary center in South Korea.Methods: We retrospectively reviewed the charts of all consecutive patients with DTC treated during ≥6 months with lenvatinib (February 2016–April 2018) and sorafenib (January 2014–April 2018) at Gangnam Severance Hospital. Patients were tre…
Abemaciclib: safety and effectiveness of a unique cyclin-dependent kinase inhibitor
2020
Introduction: The discovery and the clinical availability of novel cyclin-dependent kinases 4 and 6 inhibitors have profoundly changed the therapeutic scenario of metastatic hormone receptor-positive breast carcinoma. Among these inhibitors, abemaciclib can induce potent and sustained cell cycle arrest and immune system stimulation. Areas covered: This review summarizes the safety profile and clinical efficacy data on abemaciclib alone or in combination with aromatase inhibitors or fulvestrant in metastatic hormone receptor-positive breast carcinoma. The management of patients treated with abemaciclib is the object of this paper. Expert opinion: As shown in phase 2 and 3 clinical trials on …
Discovery of a new class of sortase a transpeptidase inhibitors to tackle gram-positive pathogens: 2-(2-phenylhydrazinylidene)alkanoic acids and rela…
2016
A FRET-based random screening assay was used to generate hit compounds as sortase A inhibitors that allowed us to identify ethyl 3-oxo-2-(2-phenylhydrazinylidene)butanoate as an example of a new class of sortase A inhibitors. Other analogues were generated by changing the ethoxycarbonyl function for a carboxy, cyano or amide group, or introducing substituents in the phenyl ring of the ester and acid derivatives. The most active derivative found was 3-oxo-2-(2-(3,4dichlorophenyl)hydrazinylidene)butanoic acid (2b), showing an IC50 value of 50 µM. For a preliminary assessment of their antivirulence properties the new derivatives were tested for their antibiofilm activity. The most active compo…
Prevalence of aphthous stomatitis in patients with inflammatory bowel disease after the treatment with monoclonal antibodies: a systematic review and…
2022
Currently, the most frequently employed therapies in the treatment of inflammatory bowel diseases (IBD), i.e., Crohn's Disease (CD), Ulcerative Colitis (UC) or unclassified IBD (IBD-U) are monoclonal anti-TNFs and anti-integrin therapies, such as vedolizumab (VDZ). Forty-seven per cent of these patients present extra-intestinal manifestations, the second most prevalent being aphthous stomatitis (AS). The present study aims to investigate which of the two therapies is associated with a lower prevalence of AS after treatment. An electronic search of the MEDLINE (via PubMed), Web of Science, SCOPUS, LILACS and OpenGrey databases was carried out. The criteria used were those described by the PR…