The Sigma1 receptor (Sigma1) is an endoplasmic reticulum (ER) integral membrane protein that is highly expressed in a number of cancer cell lines. Small molecule compounds targeting Sigma1 (Sigma1 ...ligands) inhibit cancer cell proliferation and induce apoptotic cell death in vitro and inhibit tumor growth in xenograft experiments. However, the cellular pathways activated by Sigma1 protein-ligand interaction are not well defined. Here, we find that treatment with some Sigma1 ligands induces ER stress and activates the unfolded protein response (UPR) in a dose- and time-responsive manner in a range of adenocarcinoma cell lines. Autophagy is engaged after extended treatment with Sigma1 ligands, which suggests that protracted UPR results in autophagy as a secondary response. Inhibition of UPR by RNAi-mediated knockdown of inositol-requiring enzyme 1α and activating transcription factor 4 abrogates autophagosome formation, as does knockdown of essential autophagy gene products Beclin1 and autophagy protein 5. Knockdown of Sigma1 also suppresses IPAG 1-(4-iodophenyl)-3-(2-adamantyl) guanidine induced UPR marker and autophagosome levels, indicating that this response is indeed Sigma1-mediated. We find that UPR activation precedes autophagosome formation and autophagy precedes apoptosis in Sigma1 ligand-treated cells. These processes are reversible, and washout of IPAG before cell death results in a return of autophagosomes and UPR markers toward basal levels. However, inhibition of Sigma1 ligand-induced UPR or autophagy accelerates apoptotic cell death. Together, these data suggest that UPR and autophagy are engaged as primary and secondary cytoprotective responses, respectively, to Sigma1 ligand-induced disruption of cancer cell protein homeostasis.
The treatment strategy incorporates a collaborative heart team approach with interventional cardiologists and a surgeon, who discuss the patient status and coronary anatomy; with intent to treat the ...culprit vessel first. 26% had both surgery and stenting during the same hospitalization but not on the same day. rHCR benefits include little hesitation to perform surgery even on patients taking dual antiplatelet therapy (DAPT), mainly Clopidogrel, because of the precision and accuracy with robotic technology.
Caco-2 monolayers were used to contrast the bidirectional transport of iron chelators and their chelates and to estimate fundamental kinetics associated with their intestinal absorption.
...Bidirectional transport was studied at 37 degrees C and pH 7.4 using 500-microM concentrations. Monolayer integrity was tested via transepithelial electrical resistance and sodium fluorescein permeability. Apical and basolateral analysis provided mass balance evidence. Apparent permeability coefficient (P(app)) served to rank and compare molecules and estimate in vivo bioavailability. Model-dependent rate constants defined cellular influx and efflux.
1) P(app) ranked in decreasing order for chelators from directional transport studies were CP363 > deferiprone> ICL670 > CP502 > deferoxamine (DFO). 2) Fe(CP502)(3), Fe(ICL670)(2), and FeDFO were not measurable in receiving chambers, whereas Fe(deferiprone)(3) and Fe(CP363)(3) were detected in both directions. 3) CP363 was transported significantly faster from the basolateral to the apical direction than the converse. 4) Mass balance of donor and receiver chambers gave approximately 100% recovery in all cases. 5) Kinetic analysis supports the view that the Caco-2 chelator efflux constants are generally greater than their influx constants.
Caco-2 cells are useful in screening iron chelators and chelates and estimating bioavailabilities. Structure and distribution coefficients partially predict passive transport through Caco-2 monolayers.
► Sigma1 ligand treatment mediates decrease in tumor cell mass. ► Identification of a Sigma1 ligand with reversible translational repressor actions. ► Demonstration of a role for Sigma1 in cellular ...protein synthesis.
Treatment with sigma1 receptor (Sigma1) ligands can inhibit cell proliferation in vitro and tumor growth in vivo. However, the cellular pathways engaged in response to Sigma1 ligand treatment that contribute to these outcomes remain largely undefined. Here, we show that treatment with putative antagonists of Sigma1 decreases cell mass. This effect corresponds with repressed cap-dependent translation initiation in multiple breast and prostate cancer cell lines. Sigma1 antagonist treatment suppresses phosphorylation of translational regulator proteins p70S6K, S6, and 4E-BP1. RNAi-mediated knockdown of Sigma1 also results in translational repression, consistent with the effects of antagonist treatment. Sigma1 antagonist mediated translational repression and decreased cell size are both reversible. Together, these data reveal a role for Sigma1 in tumor cell protein synthesis, and demonstrate that small molecule Sigma1 ligands can be used as modulators of protein translation.
The fractional concentration of exhaled nitric oxide (Feno) is a marker of asthmatic airway inflammation. We determined the dose response and the reproducibility of the Feno fall following inhaled ...beclomethasone dipropionate (iBDP) therapy in nonsteroid-treated asthmatic patients.
Study A: For four 1-week periods (period 1 to period 4), the following regimens were administered in sequential order to 15 nonsteroid-treated asthmatic patients: period 1, placebo; period 2, 100 μg/d of iBDP; period 3, 400 μg/D of iBDP; and period 4, 800 μg/d of iBDP. Spirometry, Feno, and provocative concentration of methacholine resulting in a 20% fall in FEV1 (PC20) were measured at each of five visits (visit 1 to visit 5). Study B: During four periods, 12 nonsteroid-treated asthmatic patients received placebo treatment for 7 days (period 1), 200 μg/d of iBDP for 14 days (period 2), washout on placebo treatment until the Feno was within 15% of baseline (period 3), and 200 μg/d of iBDP for 14 days (period 4).
Study A: Mean FEV1 rose progressively from 3.10 L (visit 1) to 3.41 L (visit 5; p = 0.001). All iBDP doses caused a significant FEV1 rise compared to placebo treatment, but with no significant separation of doses using FEV1. Feno geometric mean (95% confidence limits) fell progressively from 103.5 parts per billion (ppb) (78.5 to 136.7) to 37.4 ppb (29.1 to 48.0) from visit 1 to visit 5 (p = 0.001). All doses of iBDP resulted in a significant change in Feno from placebo treatment, but with significant separation of only the 100-μg and 800-μg doses by Feno. Geometric mean (95% confidence limits) PC20 rose progressively from 0.01 mg/mL (0.00 to 0.19) to 0.48 mg/mL (0.01 to 8.1) from visit 1 to visit 5 (p = 0.002). All doses of iBDP resulted in a significant change in PC20 from baseline or placebo treatment, but with no significant separation of active iBDP doses using PC20. Study B: Feno fell from 111.56 ppb (80.3 to 155.1) to 66.3 ppb (49.2 to 89.5; p < 0.001) from period 1 to period 2, and from 110.2 ppb (79.3 to 153.1) to 61.7 ppb (42.9 to 88.8; p < 0.001) from period 3 to period 4. There were no significant differences between Feno in period 1 and period 3 (p = 0.83) or between period 2 and period 4 (p = 0.220).
Feno was superior to FEV1 and PC20 in separating doses of iBDP. The fall in Feno after two identical administrations of iBDP separated by placebo washout was highly reproducible.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The occurrence of in vivo iron toxicity in the human body can be categorized into iron overload and non-iron overload conditions. Iron overload conditions are common in β-thalassemia and hereditary ...hemochromatosis patients, and anthracycline mediated cardiotoxicity is an example of a non-iron overload condition in cancer patients, in which the toxicity is iron-dependent. While hundreds of iron chelators have been evaluated in animal studies, only a few have been studied in humans. Examples of iron chelator drugs are desferrioxamine (DFO), deferiprone (L1), and dexrazoxane (ICRF 187). The compound ICL670 has completed phase II clinical trials and a phase III trial is planned in 2003. TriapineTM is currently in phase II clinical trial as an anticancer agent. CP502, GT56-252, NaHBED, and MPB0201 are examples of new chelators in preclinical / clinical development. In the past decade, many new viable utilities for iron chelators have been reported. This includes the use of iron chelators as antiviral, photoprotective, antiproliferative, and antifibrotic agents. This review will focus on the status of drug development for the treatment of iron overload in patients with β-thalassemia and the potential use of iron chelators in the prevention and treatment of other diseases.
A better understanding of the biological roles and the pathological consequences of thiol-dependent enzymes has emerged in recent years, and hence considerable progress has been made in identifying ...and delineating cysteine proteases that can be considered promising drug targets from those involved in housekeeping functions. Cysteine proteases have been implicated in a wide variety of disease processes ranging from cardiovascular, inflammatory, viral and immunological disorders to cancer. The first milestone in drug development of cysteine protease inhibitors has probably been reached, as IDN-6556 (a broad spectrum caspase inhibitor) has recently received Orphan Drug label by the U.S. Food and Drug Administration for use in the treatment of the patients undergoing liver transplantation and other solid organ transplantation. IDN-6556, which blocks apoptosis, is in Phase II human clinical trial in patients undergoing liver transplantation. In addition, more than ten cysteine protease inhibitors are presently at various phases of clinical development/trials for diverse diseases. This review emphasises on the new development from the literature reports since the year 2000 in the exploration of potential cysteine proteases as prospective drug targets, and the investigation of promising inhibitors that can potentially be developed for the treatment of human diseases. Transglutaminases, another class of thiol-dependent enzymes, are not discussed here.
To the Editor:
Olivieri et al. (Aug. 13 issue)
1
retrospectively evaluated liver-biopsy specimens from patients with thalassemia who were treated with deferiprone and concluded that progression of ...fibrosis in 5 of 14 patients was due to the drug. The authors minimized the potential role of known factors that could, on their own, explain the progression of fibrosis in the five patients and the fact that many had received inadequate chelation therapy before they started taking deferiprone. Fibrosis and even cirrhosis are prominent in patients with thalassemia, as illustrated by the fact that 3 of 18 patients had cirrhosis before treatment . . .
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