Ubiquitin-proteasome system (UPS) plays an essential role in eukaryotic protein cycle,the dysregulation of which can lead to tumorigenesis.Increased activities of UPS have been observed in the patients with cancers including leukemia.UPS inhibitors can kill cancer cells by affecting ubiquitin-ligating enzyme E3,deubiquitinase,and protein degradation active sites of UPS.Therefore,UPS inhibitors have emerged as an important therapy for treating hematological malignancies,while they are rarely applied in the treatment of acute myeloid leukemia.This paper summarizes the research progress in the inhibitors affecting the protein ubiquitination at different stages of acute myeloid leukemia,aiming to provide new clues for the clinical treatment of acute myeloid leukemia.
Humans ; Proteasome Inhibitors/therapeutic use* ; Ubiquitin/metabolism* ; Proteasome Endopeptidase Complex/metabolism* ; Ubiquitination ; Leukemia, Myeloid, Acute/drug therapy*

OBJECTIVETo review this efficacy and safety of bortezomib, a proteasome inhibitor, in the setting of the sensitized transplant candidate.

DATA SOURCESThe data used in this review were from articles published (PubMed) between 2000 to 2010. Additionally abstracts from medical meetings related to transplant were also used.

STUDY SELECTIONArticles were selected if they were trial results or case studies for the use of bortezomib in the sensitized patient population.

RESULTSThe early data using bortezomib as a part of desensitization regimens has shown success. Although one cycle (4 doses) of bortezomib seems to have affect on many patients, it also seems likely that to provide complete desensitization multiple cycles will be required. Regarding safety, bortezomib has been shown to have minimal side effects. The most common side effects reported are those of thrombocytopenia and anemia. These side effects are dose related and self limiting upon discontinuation of the treatment.

CONCLUSIONSBortezomib with plasmapheresis is a promising new alternative to desensitization protocols that use either high dose intravenous immune globulin (IVIG) or low dose IVIG and plasmapheresis. The efficacy on antibody reduction looks to be batter that that of the IVIG based regimens without significant addition toxicity. The results of ongoing prospective trials are positive and their complete results are greatly anticipated.

Boronic Acids ; therapeutic use ; Bortezomib ; Graft Rejection ; immunology ; prevention & control ; Humans ; Protease Inhibitors ; therapeutic use ; Proteasome Endopeptidase Complex ; metabolism ; Pyrazines ; therapeutic use ; Transplants ; adverse effects

This study aims to identify the novel biomarkers of cold-dampness syndrome(RA-Cold) of rheumatoid arthritis(RA) by gene set enrichment analysis(GSEA), weighted gene correlation network analysis(WGCNA), and clinical validation. Firstly, transcriptome sequencing was carried out for the whole blood samples from RA-Cold patients, RA patients with other traditional Chinese medicine(TCM) syndromes, and healthy volunteers. The differentially expressed gene(DEG) sets of RA-Cold were screened by comparison with the RA patients with other TCM syndromes and healthy volunteers. Then, GSEA and WGCNA were carried out to screen the key DEGs as candidate biomarkers for RA-Cold. Experimentally, the expression levels of the candidate biomarkers were determined by RT-qPCR for an independent clinical cohort(not less than 10 cases/group), and the clinical efficacy of the candidates was assessed using the receiver operating characteristic(ROC) curve. The results showed that 3 601 DEGs associated with RA-Cold were obtained, including 106 up-regulated genes and 3 495 down-regulated genes. The DEGs of RA-Cold were mainly enriched in the pathways associated with inflammation-immunity regulation, hormone regulation, substance and energy metabolism, cell function regulation, and synovial pannus formation. GSEA and WGCNA showed that recombinant proteasome 26S subunit, ATPase 2(PSMC2), which ranked in the top 50% in terms of coefficient of variation, representativeness of pathway, and biological modules, was a candidate biomarker of RA-Cold. Furthermore, the validation results based on the clinical independent sample set showed that the F1 value, specificity, accuracy, and precision of PSMC2 for RA-Cold were 70.3%, 61.9%, 64.5%, and 81.3%, respectively, and the area under the curve(AUC) value was 0.96. In summary, this study employed the "GSEA-WGCNA-validation" integrated strategy to identify novel biomarkers of RA-Cold, which helped to improve the TCM clinical diagnosis and treatment of core syndromes in RA and provided an experimental basis for TCM syndrome differentiation.
Humans ; Arthritis, Rheumatoid/drug therapy* ; Biomarkers/metabolism* ; Medicine, Chinese Traditional ; Gene Expression Profiling/methods* ; Computational Biology ; Gene Regulatory Networks ; ATPases Associated with Diverse Cellular Activities/therapeutic use* ; Proteasome Endopeptidase Complex/therapeutic use*

The inhibition of protein degradation through the ubiquitin-proteasome pathway is a recently developed approach to cancer treatment which extends the range of cellular target for chemotherapy. This therapeutic strategy is very interesting since the proteasomes carry out the regulated degradation of unnecessary or damaged cellular proteins, a process that is dysregulated in many cancer cells. Based on this hypothesis, the proteasome complex inhibitor Bortezomib was approved for use in multiple myeloma patients by FDA in 2003. Drug discovery programs in academy and the pharmaceutical industry have developed a range of synthetic and natural inhibitors of the 20S proteasome core particle that have entered human clinical trials as significant anti-cancer leads. The main results from the use of proteasome inhibition in cancer chemotherapy, the structure of several proteasome inhibitors and their synthesis is going to be reviewed in this paper.
Acetylcysteine ; analogs & derivatives ; chemical synthesis ; chemistry ; Antineoplastic Agents ; chemical synthesis ; classification ; therapeutic use ; Boronic Acids ; chemical synthesis ; chemistry ; therapeutic use ; Bortezomib ; Cysteine Proteinase Inhibitors ; chemical synthesis ; classification ; Dipeptides ; chemical synthesis ; chemistry ; Humans ; Multiple Myeloma ; drug therapy ; enzymology ; Peptides, Cyclic ; chemical synthesis ; chemistry ; Proteasome Endopeptidase Complex ; metabolism ; Proteasome Inhibitors ; Pyrazines ; chemical synthesis ; chemistry ; therapeutic use ; Ubiquitin ; antagonists & inhibitors ; metabolism

OBJECTIVETo study the effect of human proteasome subunit Α7(PSMA7)gene silencing by small interfering RNA(siRNA)on human myeloid leukemia cell line K562.

METHODSPSMA7 gene-specific siRNA was chemically synthesized and transfected into K562 cell line by HiPerFect. The expression level of PSMA7 protein was detected by Western blot analysis. Cell proliferation was determined by MTS and cell counting. Cell cycle distribution was measured by flow cytometry. The expressions of Cyclin A, D, and E were detected by Western blot analysis. The apoptotic ratio was determined by flow cytometry.

RESULTSPSMA7 protein was evidently silenced 48 hours after transfection of the PSMA7-specific siRNA into K562 cell line. The proliferation of the cells was markedly inhibited, and the percentage of S phase cells decreased. However, no apoptosis was observed. The expressions of Cyclin A and E were down-regulated.

CONCLUSIONKnockdown of PSMA7 down-regulates the expression of Cyclin A and E and thus decreases the proportion of cells in S phase as a result, the proliferation of K562 cell line is inhibited.

Apoptosis ; Cell Cycle ; Cell Line ; Cell Proliferation ; genetics ; Down-Regulation ; Gene Knockdown Techniques ; Humans ; K562 Cells ; Proteasome Endopeptidase Complex ; genetics ; metabolism ; RNA, Messenger ; RNA, Small Interfering ; therapeutic use ; Transfection

Many major neurodegenerative diseases are associated with proteins misfolding and aggregation, which are also called "neurodegenerative conformational disease". The interaction of gene mutation and environmental factors are probably primary events resulting in oligomer and aggregate formations of proteins. Moreover, the dysfunctions of protein control systems, i.e. the ubiquitin-proteasome system and autophagy-lysosomal system, also contribute to the neurodegenerative process. The present review mainly summarizes protein misfolding and aggregation in the development of neurodegenerative conformational disease and the underling mechanisms, as well as upregulation of heatshock proteins as a promising treatment method for this kind of disease.
Alzheimer Disease ; drug therapy ; genetics ; metabolism ; pathology ; Animals ; Annona ; chemistry ; Autophagy ; Benzeneacetamides ; isolation & purification ; therapeutic use ; Heat-Shock Proteins ; metabolism ; physiology ; Humans ; Mutation ; Neurodegenerative Diseases ; drug therapy ; genetics ; metabolism ; pathology ; Parkinson Disease ; drug therapy ; genetics ; metabolism ; pathology ; Phenols ; isolation & purification ; therapeutic use ; Plants, Medicinal ; chemistry ; Proteasome Endopeptidase Complex ; metabolism ; Protein Folding ; Ubiquitin ; metabolism

Post-translational degradation of protein plays an important role in cell life. We employed chimeric molecules (dihydrotestosterone-based proteolysis-targeting chimeric molecule [DHT-PROTAC]) to facilitate androgen receptor (AR) degradation via the ubiquitin-proteasome pathway (UPP) and to investigate the role of AR in cell proliferation and viability in androgen-sensitive prostate cancer cells. Western blot analysis and immunohistochemistry were applied to analyse AR levels in LNCaP cells after DHT-PROTAC treatment. Cell counting and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) cell viability assay were used to evaluate cell proliferation and viability after AR elimination in both LNCaP and PC-3 cells. AR was tagged for elimination via the UPP by DHT-PROTAC, and this could be blocked by proteasome inhibitors. Degradation of AR depended on DHT-PROTAC concentration, and either DHT or an ALAPYIP-(arg)(8) peptide could compete with DHT-PROTAC. Inhibition of cell proliferation and decreased viability were observed in LNCaP cells, but not in PC-3 or 786-O cells after DHT-PROTAC treatment. These data indicate that AR elimination is facilitated via the UPP by DHT-PROTAC, and that the growth of LNCaP cells is repressed after AR degradation.
Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cell Survival ; drug effects ; Dihydrotestosterone ; pharmacology ; Dose-Response Relationship, Drug ; Humans ; Male ; Prostatic Neoplasms ; drug therapy ; metabolism ; pathology ; Proteasome Endopeptidase Complex ; metabolism ; Receptors, Androgen ; metabolism ; Recombinant Fusion Proteins ; pharmacology ; therapeutic use ; Signal Transduction ; drug effects ; Ubiquitin ; metabolism