ABSTRACT
PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors and hormones. It has been implicated in the control of cell cycle progression and apoptosis and its overexpression has been associated with various kinds of lymphoid and hematopoietic malignancies. The activity of PIM1 is dependent on the phosphorylation of several targets involved in transcription, cell cycle and apoptosis. We have recently observed that PIM1 interacts with ribosomal protein (RP)S19 and cosediments with ribosomes. Defects in ribosome synthesis (ribosomal stress) have been shown to activate a p53-dependent growth arrest response. To investigate if PIM1 could have a role in the response to ribosomal stress, we induced ribosome synthesis alterations in TF-1 and K562 erythroid cell lines. We found that RP deficiency, induced by RNA interference or treatment with inhibitor of nucleolar functions, causes a drastic destabilization of PIM1. The lower level of PIM1 induces an increase in the cell cycle inhibitor p27(Kip1) and blocks cell proliferation even in the absence of p53. Notably, restoring PIM1 level by transfection causes a recovery of cell growth. Our data indicate that PIM1 may act as a sensor for ribosomal stress independently of or in concert with the known p53-dependent mechanisms.
Subject(s)
Cell Cycle/physiology , Proto-Oncogene Proteins c-pim-1/metabolism , Ribosomal Proteins/metabolism , Ribosomes/metabolism , Stress, Physiological , Blotting, Western , Cell Line, Tumor , Cell Proliferation , Cell Separation , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Flow Cytometry , Gene Expression , Gene Expression Regulation , Humans , Proto-Oncogene Proteins c-pim-1/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/physiology , Stress, Physiological/physiology , Tumor Suppressor Protein p53/metabolismSubject(s)
ATP-Binding Cassette Transporters/metabolism , Apoptosis , GTP-Binding Proteins/metabolism , Transglutaminases/metabolism , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/genetics , Animals , Apoptosis/genetics , GTP-Binding Proteins/deficiency , GTP-Binding Proteins/genetics , Lipids/blood , Lipoproteins/blood , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/immunology , Mice , Mice, Knockout , Phagocytosis/physiology , Phenotype , Protein Glutamine gamma Glutamyltransferase 2 , Transglutaminases/deficiency , Transglutaminases/geneticsABSTRACT
We have studied the effect of indobufen, a cyclo-oxygenase blocking agent which has proved useful in patients with obstructive vascular disease, on red blood cell (RBC) filterability in vitro and in a pilot study ex vivo. The addition of indobufen in vitro to blood samples from 10 healthy volunteers did not significantly modify RBC deformability. We evaluated the ex vivo effect of indobufen (200 mg bd) in 14 patients with obstructive vascular disease. A significant improvement in RBC deformability was noted on the 5th, 14th, and 28th days of treatment, 2 h after the morning dose. Acetylsalicylic acid given to 6 similar patients had no effect suggesting that the positive haemorheological effect of indobufen is probably not linked to its cyclooxygenase blocking effect.
Subject(s)
Erythrocyte Deformability/drug effects , Phenylbutyrates/pharmacology , Aspirin/pharmacology , Drug Interactions , Humans , In Vitro Techniques , Isoindoles , Vascular Diseases/bloodABSTRACT
A trial was carried out on 30 patients with cerebrovascular disease to evaluate the effect of indobufen, a new antiplatelet drug, on some platelet functions and coagulation, and its tolerance, after 12-months' treatment. From the results of the present study it appears that 2 hours after administration indobufen was able to reduce platelet aggregation induced by ADP, platelet adhesiveness, circulating platelet aggregates, and to increase bleeding time. These differences remained constant throughout the treatment period. Except in 3 patients, between the 8th and 12th months, who suffered an ischaemic attack with no aftermaths, no cerebrovascular ischaemic attacks occurred during indobufen treatment. No side-effects were observed. The data indicate that indobufen is a well-tolerated drug in all situations requiring antiplatelet treatment.
Subject(s)
Blood Platelets/drug effects , Cerebrovascular Disorders/drug therapy , Phenylbutyrates/therapeutic use , Adult , Aged , Cerebrovascular Disorders/blood , Clinical Trials as Topic , Female , Humans , Isoindoles , Male , Middle Aged , Phenylbutyrates/adverse effects , Phenylbutyrates/pharmacology , Platelet Adhesiveness/drug effects , Platelet Aggregation/drug effectsABSTRACT
In a randomized double-blind crossover study in 12 patients with atherosclerotic disease, the effect of 2 dosages (100 and 200 mg twice daily) of indobufen, a new synthetic inhibition of platelet aggregation, on some platelet functions, coagulation and fibrinolysis tests was investigated. Regardless of the dosage used, indobufen was shown to induce a prompt normalization of the enhanced platelet aggregation of these patients. The effect lasted for the entire period of drug administration and in 50% of patients a normal platelet aggregation was maintained until the fourth day after discontinuation of the drug. Indobufen was also able to reduce platelet adhesiveness and to lengthen bleeding time, especially when the higher dosage was used.
Subject(s)
Arterial Occlusive Diseases/drug therapy , Phenylbutyrates/therapeutic use , Platelet Adhesiveness/drug effects , Platelet Aggregation/drug effects , Aged , Antithrombins/pharmacology , Blood Coagulation/drug effects , Double-Blind Method , Fibrinolysis/drug effects , Humans , Isoindoles , Male , Middle Aged , Phenylbutyrates/adverse effects , Time FactorsSubject(s)
Gastric Emptying/drug effects , Metoclopramide/analogs & derivatives , Metoclopramide/pharmacology , Adult , Aged , Clinical Trials as Topic , Female , Humans , Male , Middle AgedABSTRACT
Possible interactions between indoprofen (IP) and Warfarin Na (W) were studied in 18 patients under chronic anticoagulant treatment, according to a cross-over, double-blind design, comparing 600 mg daily of IP with placebo (PL). In all subjects the dosage of W was kept constant throughout the study (21 days). No significant differences were found between IP and PL either on coagulation parameters or on platelet count and platelet adhesiveness. Afte IP a significant decrease in platelet aggregation (induced by ADP and adrenaline) was observed. The results suggest that indoprofen can be administered to patients under anticoagulant treatment, although frequent checks of the coagulation parameters are advisable in these cases.
