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*

The proteasome is primarily responsible for intracellular protein degradation. The abnormality of its activity is sign of tumorigenesis. It was confirmed that proteasome inhibitors have activities against a variety of malignancies. Bortezomib, the first proteasome inhibitor, obtained permission of clinical trial and on sale. Multiple myeloma patients treated with bortezomib have gained a high overall response rate and complete remission rate. A lot of studies on effects of proteasome inhibitors on leukemias, including plasma cell leukemia; chronic lymphocytic leukemia, adult T cell lymphoma/leukemia, chronic myeloid leukemia and acute myeloid leukemia, were reviewed in this article.
Animals ; Boronic Acids ; therapeutic use ; Bortezomib ; Humans ; Leukemia ; drug therapy ; enzymology ; Multiple Myeloma ; drug therapy ; Protease Inhibitors ; therapeutic use ; Proteasome Inhibitors ; Pyrazines ; therapeutic use

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

OBJECTIVES: There is less clinical data on multiple myeloma (MM) in China, and the aim of this study was to collect and analyze the clinical data of newly diagnosed multiple myeloma (NDMM) patients in Hunan Province during 1 year, to understand the real clinical features and treatment outcome for Hunan Province patients with MM, and to strengthen the understanding of the standardized diagnosis process and treatment plan of MM. METHODS: The clinical data of 529 patients with NDMM in 12 large-scale general hospitals in Hunan Province from January 1 to December 31, 2019 were collected and analyzed, including baseline data, treatment regimens, duration of treatment, and adverse reactions. The clinical characteristics, treatment, and safety of patients were analyzed by SPSS 21.0. RESULTS: Among the 529 NDMM patients, the age was 33-90 (median 64) years and the male-female ratio was 1.38꞉1. The clinical features ranged from high to low were as follows: Bone pain (77.7%), anemia (66.8%), renal insufficiency (40.6%), hypercalcemia (15.1%). Typing: IgG 46.5%, IgA 24.6%, IgD 2.6%, IgM 0.8%, light chain 15.7%, double clone 3.0%, no secretion 0.6%, absence 6.2%. Staging: Durie-Salmon stage I, II, and III were 4.5%, 10.6%, 77.3%, respectively, and 40 cases (7.6%) missed this data. International Staging System (ISS) stage I, II, and III were 10.4%, 24.4%, and 47.6%, respectively, and 93 cases (17.6%) were missing. Revised International Staging System (R-ISS) stage I, II, and III were 5.5%, 27.0%, 23.1%, respectively, and 235 cases (44.4%) missed this data. Among the 98 NDMM patients in the Third Xiangya Hospital, Central South University, Durie-Salmon (DS) stage missing 2.0%, ISS stage missing 12.3%, and R-ISS stage missing 12.3%.Treatment: Among the 529 patients,475 received treatment, the rate of treatment was 89.8%; 67.4% of the patients were able to complete four courses of chemotherapy at induction phase, 90.3% of the patients received proteasome inhibitor based combination chemotherapy regimen more than once, 67.2% received immunomodulator based regimen more than once, and 59.8% of the patients received proteasome inhibitor and immunomodulator based combination chemotherapy regimen more than once. Curative: Overall response rate (ORR) and high quality response rate (HQR) of the 4-course group were better than those of the 2-course group (ORR: 85% vs 65%, P=0.006; HQR: 68.3% vs 24.0%, P<0.001). The HQR of the standard chemotherapy group was better than that of the non-standard chemotherapy group (65.1% vs 48.2%, P=0.035). Adverse reactions during treatment included hematologic toxicity (17.5%), peripheral neuropathy (24.8%), gastrointestinal adverse events (23.8%), pulmonary infection (25.9%), herpes zoster (4.6%), and venous thrombotic events (1.7%). CONCLUSIONS In 2019, the missed diagnosis rate of MM patients was high, the medium age of diagnosis was older, and the accuracy of patient diagnosis was not high. There is a great difference among medical centers, especially in the stage and risk stratified, nearly half of NDMM patients are not diagnosed with R-ISS stage; the lack of cytogenetic data needs to be supplemented by follow-up studies. A high proportion of patients with NDMM present with bone pain and anemia.Patients received treatment have higher use of chemotherapy regimens containing proteasome inhibitors and/or immunomodulators, but there is a significant gap among different medical centers, and standardized treatment needs to be strengthened. The safety during chemotherapy is controllable.
Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Female ; Humans ; Immunologic Factors/therapeutic use* ; Male ; Middle Aged ; Multiple Myeloma/therapy* ; Neoplasm Staging ; Pain ; Prognosis ; Proteasome Inhibitors/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

Multiple myeloma (MM) is a common plasma cell malignancy, accounting for the second largest hematological malignancy. Proteasome inhibitors represented by bortezomib (BTZ) have been the main treatment for patients with newly diagnosed and relapsed or refractory myeloma in nearly two decades. Although BTZ has improved the prognosis of MM patients, MM remains incurable in most patients, mainly because MM cells become resistant to BTZ. This review is to better understand the mechanism of MM resistance to BTZ and explore possible new therapeutic strategies.
Humans ; Bortezomib/therapeutic use* ; Multiple Myeloma/pathology* ; Proteasome Inhibitors/pharmacology* ; Prognosis ; Plasma Cells/pathology* ; Drug Resistance, Neoplasm ; Antineoplastic Agents/pharmacology* ; Cell Line, Tumor

PURPOSE: Although the proteasome inhibitor known as bortezomib can modulate the inflammatory process through the nuclear factor-kappa B signaling pathway, the immunomodulatory effect of pre-incubated bortezomib has not been fully evaluated for inflammation by infectious agents. Therefore, we evaluated the effect of bortezomib on the expression of inflammatory cytokines and mediators in macrophage cell lines and on survival in a murine peritonitis sepsis model. MATERIALS AND METHODS: Bortezomib was applied 1 hr before lipopolysaccharide (LPS) stimulation in RAW 264.7 cells. The cecal ligation and puncture (CLP) experiments were performed in C57BL/6J mice. RESULTS: Pre-incubation with bortezomib (25 nM or 50 nM) prior to LPS (50 ng/mL or 100 ng/mL) stimulation significantly recovered the number of viable RAW 264.7 cells compared to those samples without pre-incubation. Bortezomib decreased various inflammatory cytokines as well as nitric oxide production in LPS-stimulated cells. The 7-day survival rate in mice that had received bortezomib at 0.01 mg/kg concentration 1 hr prior to CLP was significantly higher than in the mice that had only received a normal saline solution of 1 mL 1 hr prior to CLP. In addition, the administration of bortezomib at 0.01 mg/kg concentration 1 hr before CLP resulted in a significant decrease in inflammation of the lung parenchyma. Collectively, pretreatment with bortezomib showed an increase in the survival rate and changes in the levels of inflammatory mediators. CONCLUSION: These results support the possibility of pretreatment with bortezomib as a new therapeutic target for the treatment of overwhelming inflammation, which is a characteristic of severe sepsis.
Animals ; Boronic Acids/administration & dosage/pharmacology/*therapeutic use ; Cecum/*pathology ; Cell Adhesion Molecules/metabolism ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chymotrypsin/metabolism ; Cytokines/*metabolism ; Disease Models, Animal ; Inflammation Mediators/*metabolism ; Ligation ; Lipopolysaccharides/pharmacology ; Lung/drug effects/metabolism/pathology ; Male ; Mice, Inbred C57BL ; Nitric Oxide/metabolism ; Proteasome Inhibitors/pharmacology ; Punctures ; Pyrazines/administration & dosage/pharmacology/*therapeutic use ; Sepsis/*drug therapy