The dichotomous role of immunoproteasome in cancer: Friend or foe?

Immunoproteasome is a variant of proteasome with structural differences in 20S subunits optimizing them for the production of antigenic peptides with higher binding affinity to major histocompatibility complex (MHC)-I molecules. Apart from this primary function in antigen presentation, immunoproteasome is also responsible for the degradation of proteins, both unfolded proteins for the maintenance of protein homeostasis and tumor suppressor proteins contributing to tumor progression. The altered expression of immunoproteasome is frequently observed in cancers; however, its expression levels and effects vary among different cancer types exhibiting antagonistic roles in tumor development. This review focuses on the dichotomous role of immunoproteasome in different cancer types, as well as summarizes the current progression in immunoproteasome activators and inhibitors. Specifically targeting immunoproteasome may be a beneficial therapeutic intervention in cancer treatment and understanding the role of immunoproteasome in cancers will provide a significant therapeutic insight for the prevention and treatment of cancers.

Ixazomib-Based Regimen Followed by Autologous Hematopoietic Stem Cell Transplantation in the Treatment of POEMS Syndrome / 中国实验血液学杂志

OBJECTIVE@#To investigate the safety and efficacy of a new proteasome inhibitor Ixazomib followed by autologous hematopoietic stem cell transplantation (AHSCT) in the treatment of POEMS syndrome.@*METHODS@#The clinical manifestations, diagnosis and treatment process and follow-up results of 4 patients with POEMS syndrome who were treated with Ixazomib-based regimen combined with AHSCT in Wuhan No.1 Hospital from February 2018 to July 2020 were analyzed retrospectively. All patients were male, aged from 37-54 years old, with varying degrees of peripheral neuropathy, organ enlargement (liver, spleen or lymph nodes), circulatory overload (peripheral edema and/or pleural effusion), osteosclerosis, endocrine diseases (thyroid, gonads, etc.), skin changes (pigmentation, hemangioma, white nails, etc.), M protein, papilledema and other clinical manifestations and characteristics at the time of initial treatment. Two patients were pathologically diagnosed as hyaline vascular Castleman disease by lymph node biopsy. Three patients underwent lumbar puncture examinations and all showed elevated cerebrospinal fluid protein. All patients received at least 2 cycles of sequential AHSCT after induction chemotherapy based on ixazomib. The follow-up time was 10-28 months, and the median follow-up time was 16 months.@*RESULTS@#All cases survived. The complications were controllable during the treatment. Moreover, the clinical symptoms related to the disease were improved to a certain extent after the treatment. The levels of vascular endothelial growth factor (VEGF) showed a gradual decline.@*CONCLUSION@#Ixazomib combined with AHSCT is safe and effective in the treatment of POEMS syndrome.

Experimental study of proteasome inhibitor MG132 up-regulates Wnt/β-catenin signaling pathway to improve osteoporosis / 中国骨伤

OBJECTIVE@#To explore the mechanism of proteasome inhibitor MG132 in improving osteoporosis.@*METHODS@#Total of 32 female SD rats, weighing 220 to 250 g and 8 weeks old, were selected. They were randomly divided into 4 groups(n=8). Rats of group A and group B were cut off ovaris on both sides to make model of osteoporosis, and then they were given proteasome inhibitors MG132 and dimethyl sufoxide (DMSO) respectively. Group C was a sham group and rats were given MG132. Group D was a normal group and rats were given MG132 too. The rats were killed in batches at 6 and 12 weeks after administration, and the femoral neck tissues were obtained. Relevant data were analyzed, such as pathomorphological observation, micro-CT analysis, detection of 20S proteasome activity in tissues, and expression of Wnt and β-catenin.@*RESULTS@#Morphological observation showed that the trabecular were slightly thinner, reticulated, and occasionally interrupted in group A, while the trabecular were obviously thinner and discontinuous in group B. And the trabecular were intact and arranged reticulated in group C and D. The analysis results of bone mineral density(BMD), bone surface(BS), bone volume/total volume(BV/TV) and trabecular thickness(Tb.Th) showed that group B was worse than other groups in all parameters at different time points(P<0.05), and group A was worse than group C and group D in BS(P<0.05), there was no significant difference in all parameters between group C and group D. RFU value of 20S proteasome in group B was significantly higher than that in other groups(P<0.05). According to the results of Western blot, the gray values of Wnt protein and β-catenin protein in group A were significantly higher than those in other groups (P<0.05).@*CONCLUSION@#MG-132, a ubiquitin proteasome inhibitor, can regulate Wnt/β-catenin signaling pathway by inhibiting the degradation of β-catenin protein, and delaying the occurrence and development of osteoporosis.

Evaluation of potential hepatotoxicity induced by Bortezomib

Bortezomib, an inhibitor of 26S proteasome, is an anti-cancer therapeutic agent used in different cancer types. It leads to the arrest of the cancerous cell cycle by inhibiting angiogenesis and inducing apoptosis. Liver is the vital organ for detoxification and excretion of toxic products. The treatment with chemotherapy is a challenge, drugs are used to destroy cancer cells, but healthy cells can be affected during cancer treatment as well. The main objective of this study was to analyze the histopathological and biochemical effects of bortezomib on liver. Twenty-four female C57BL/6 mice were distributed into 4 groups, bortezomib injected treatment groups (Btz1, Btz2) and saline injected control groups (C1, C2). Bortezomib and saline were treated twice per week for 6 weeks and sacrificed at the end of one day (Btz1, C1) and 4 weeks (Btz2, C2) after the last injection. Liver samples were examined for histopathological analysis and the serum samples processed for biochemical analysis. Tissue samples were fixed, routinely processed, sectioned, and stained with Hematoxylin and Eosin (H&E). Periodic Acid-Schiff (PAS), Sudan Black staining and Masson's trichrome histochemical staining methods were performed to characterize the lesions. Histopathological analysis of the Btz1 and Btz2 groups revealed acute hepatic morphological changes such as hepatocellular swelling (cloudy swelling), necro-inflammatory reaction, and increased mononuclear polyploidy. Based on the negative staining with PAS and Sudan Black staining, hepatocellular swelling was diagnosed as hydropic degeneration. Necro-inflammatory reaction observed in the form of acute hepatitis was composed of mainly mononuclear cell infiltration accompanied by multifocal necrotic foci. Kupffer cell proliferation was observed in parallel with degenerative and necrotic changes. An Increase in hepatocellular mononuclear polyploidy visualized as hepatocytes with a single enlarged nucleus was detected in all liver sections of Btz1 and Btz2 groups. Individual cases of cholestasis (n = 1) and mild hepatic fibrosis (n = 1) were also reported. Significant elevated levels of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were detected in bortezomib treated groups. Few clinical cases reported liver injury related to bortezomib used for cancer treatment. However, the liver was not considered as a target for bortezomib treatment. Our data suggesting that bortezomib caused liver damage and induces elevations in serum levels. The reported hepatic lesions including hepatocellular swelling, acute hepatitis and mononuclear polyploidy were mainly mild and moderate in severity. The increase of polyploidy in liver tissue of mice treated with bortezomib in this study was explained as a reaction of the liver facing the drug-induced hepatic damage. The mechanism leading to the hepatotoxicity of bortezomib treatment is not known but the production of a toxic metabolite through its metabolism in the liver can be suggested. Moreover, no recovery was also observed in histopathological and biochemical analyses suggesting that the bortezomib effect is non-reversible four weeks after the drug was withdrawn. Patients should be informed about the possibility of acute drug-induced hepatitis and hepatotoxicity of this chemotherapeutic agent after the treatment.(AU)

Oxidative Stress Modulates the Expression Pattern of Peroxiredoxin-6 in Peripheral Blood Mononuclear Cells of Asthmatic Patients and Bronchial Epithelial Cells

PURPOSE: Reduction-oxidation reaction homeostasis is vital for regulating inflammatory conditions and its dysregulation may affect the pathogenesis of chronic airway inflammatory diseases such as asthma. Peroxiredoxin-6, an important intracellular anti-oxidant molecule, is reported to be highly expressed in the airways and lungs. The aim of this study was to analyze the expression pattern of peroxiredoxin-6 in the peripheral blood mononuclear cells (PBMCs) of asthmatic patients and in bronchial epithelial cells (BECs).METHODS: The expression levels and modifications of peroxiredoxin-6 were evaluated in PBMCs from 22 asthmatic patients. Phosphorylated and acetylated peroxiredoxin-6 in hydrogen peroxide-treated human BECs was detected using immunoprecipitation analysis. The expression level of peroxiredoxin-6 was also investigated in BECs treated with hydrogen peroxide. Cycloheximide and proteasome inhibitors were used to determine whether peroxiredoxin-6 is degraded by proteasomes.RESULTS: Peroxiredoxin-6 expression was significantly reduced in the PBMCs of asthmatic patients compared to control subjects. Distinct modification patterns for peroxiredoxin-6 were observed in the PBMCs of asthmatic patients using 2-dimensional-electrophoresis. The levels of phosphorylated serine and acetylated lysine in peroxiredoxin-6 were significantly increased in the BECs following hydrogen peroxide treatment. The level of peroxiredoxin-6 expression was reduced in hydrogen peroxide-stimulated BECs, presumably due to proteasomes.CONCLUSIONS: The expression of peroxiredoxin-6, which is down-regulated in the immune cells of asthmatic patients and BECs, can be modified by oxidative stress. This phenomenon may have an effect on asthmatic airway inflammation.

Progress in the treatment of multiple myeloma / 中国临床药理学与治疗学

Multiple myeloma is a malignant tumor that occurs in plasma cells. Clonal plasma cells in bone marrow proliferate abnormally and secrete monoclonal immunoglobulin or its fragment (M protein), resulting in damage to related organs or tissues. At present, with the development of new drugs, the development of cellular immunotherapy and the improvement of hematopoietic stem cell transplantation technology, the depth of remission and survival of multiple myeloma are significantly prolonged. This article reviews the latest advances in the treatment of multiple myeloma in recent years.

Effect of proteasome inhibitor Oprozomib on ovarian cancer cells to cis-platinum / 解放军医学杂志

Objective To study the enhancement of sensitivity to cisplatin (DDP) mediated by the addition of proteasome inhibitor Oprozomib (OZ) in ovarian cancer cells. Methods SKOV3/DDP and A2780/DDP cells were cultured in vitro, and the logarithmic growth phase cells were used in this study. To study the effect of OZ on drug-resistant cell viability, a series dilutions of OZ (0, 3, 9, 27, 81, 243, 729, 2181, and 6561 nmol/L) was used. The effect of DDP was also investigated with a series titrations (0, 3, 9, 27, 81, 243, 729, 2181 and 6561 nmol/L) in the presence of 50 μl of 500 nmol/L OZ. CCK-8 method was used to detect cell viability; flow cytometry was used to detect the apoptosis rate after treated with DDP+OZ. The experiments were divided into the control group and OZ group to detect the effects of OZ on the activity of proteasome chymotrypsin (CT-L), the synthesis of intracellular glutathione (GSH); the expression of intracellular glutathione synthetase (GSS) was examined using western blotting. The experiments were divided into the control group, DDP group, OZ group, DDP+OZ group, DDP+OZ+GSH group and DDP+OZ+Tempol group to detect the ROS level and apoptosis rate. Results The IC50 of OZ to SKOV3/DDP and A2780/ DDP cells were 140 and 350 nmol/L, respectively; In the presence of OZ, the IC50 of DDP to SKOV3/DDP and A2780/DDP cells were 154 and 232 nmol/L, respectively. The apoptosis rate of ovarian cancer cells increased significantly (P<0.01) after treated with DDP+OZ together. OZ can inhibit the CT-L activity of the proteasome in a dose-dependent manner and can inhibit GSH synthesis and GSS protein expression (P<0.01). The decrease of GSH level leads to the obstruction of ROS clearance, and the ROS level was significantly reduced by the ROS scavenger Tempol (P<0.05, P<0.01). Tempol significantly inhibits the apoptosis induced by DDP+OZ (P<0.01). Conclusion OZ enhanced sensitivity of SKOV3/DDP and A2780/DDP to cis-platinum by inhibiting the generation of GHS which resulted in the accumulation of ROS.

Cardiotoxicity evaluation of three novel proteasome inhibitors in zebrafish / 中国药科大学学报

@#To evaluate the cardiotoxicity of three novel proteasome inhibitors(NNU395, NNU458 and NNU459)in zebrafish, normal developmental zebrafish embryos at 6 hours post fertilization(hpf)were treated with different doses of NNU395 and NNU458 and NNU459 until 72 hpf, the zebrafish mortality was counted. Morphologic changes of the cardiovascular system were observed under a stereomicroscope, and the number of heart beats within 1 min was determined. The expression of cardiac development-related genes in zebrafish was detected by RT-qPCR(Quantitative Real-Time PCR). Results showed that NNU395, NNU458 and NNU459 increased the mortality of zebrafish in a concentration-dependent manner and the values of LC50(50% lethal concentration)were(179. 7±12. 2), (27. 5±1. 3)and(24. 4±2. 6)μmol/L, respectively. Moreover, the toxicity of our three compounds in zebrafish are less when compared with their modified precursors. Upon administration of NNU395 at the concentrations of 120- 200 μmol/L, and NNU458 or NNU459 at the concentration of 30 μmol/L, the zebrafish showed obvious pericardial edema cardiac malformation. 120- 200 μmol/L NNU395 and 0. 1- 30 μmol/L NNU458 or 10- 30 μmol/L NNU459 significantly reduced the heart rate of zebrafish. All of three compounds at the tested concentration had no significant effects on the expression of the heart development-related genes in zebrafish. Our results suggested that low concentrations of NNU395, NNU458 and NNU459 have no obvious toxicity on cardiac development of zebrafish. While, higher concentrations of them showed cardiovascular toxicity on zebrafish.

Application of novel proteasome inhibitors in treating multiple myeloma / 中国肿瘤临床

Multiple myeloma (MM) is a hematologic malignancy of clonal proliferation of plasma cells, which ranks the second in he-matologic malignancy. Proteasome is a complex enzyme in the cell, which can degrade ubiquitin-labeled proteins and regulate intracel-lular protein levels and play an important role in maintaining the stability of the intracellular environment. In recent years, with the ap-plication of new proteasome inhibitors, great progress has been achieved in MM treatment, further improving the therapeutic efficacy of myeloma.

Research progress on 26S proteasome inhibitors / 药学学报

The 26S proteasome is a 2.5 MDa complex of the protease family members and is central to a vast array of vital cellular processes including cell-cycle progression and antigen presentation. It has been proven to be a target for therapeutic agents in the treatment of cancers and autoimmune diseases. Most inhibitors are designed to target the 20S proteolytic core complex while the efforts to target the 19S regulatory particle subunits are less successful so far. This is, in part, due to the complexity of molecular architecture and poor understanding of the mechanism of this subcomplex. This review attempts to summarize the development of inhibitory molecules that target both the 20S and 19S subunits of the proteasome, especially highlight the recent progress in the proteasome structure and development of the new inhibitors.

Inhititory effect of proliferation and promotion effect of apoptosis of lactacystin combined with carboplatin on ovarian cancer SKOV3 cells / 吉林大学学报(医学版)

Objective:To study the influence of proteasome inhibitor lactacystin (LAC) and carboplatin in proliferation and apoptosis of the human ovarian cancer SKOV3 cells in vitro ,and to clarify the mechanisms. Methods:The SKOV3 ovarian cancer cells were cultured in vitro ;0,2.5,5.0,10.0 and 20.0 μmol· L-1 LAC were used to intervent the SKOV3 cells for 48 h;5 μmol·L-1 LAC was used to intervent the SKOV3 cells for 0, 24,48,and 72 h;the SKOV3 cells were divided into control group (treated without medical intervention),LAC group (treated with 5 μmol · L-1 LAC), carboplatin group (treated with 10, 20, 40 and 80 μmol · L-1 carboplatin),LAC and carboplatin group (treated with 5 μmol· L-1 LAC and 10,20,40,and 80 μmol· L-1 carboplatin,respectively).MTT method and FCM were used to detect the inhibitory rates of proliferation and apoptotic rates of the SKOV3 cells in various groups.Results:The MTT test results showed that the proliferation of the SKOV3 cells were inhibited with the prolongation of time and increasing of LAC concentration;the half inhibitory concentration (IC50 )of LAC at 48 h was 5.36 μmol · L-1 ;compared with carboplatin group,the inhibitory rates of proliferation of SKOV3 cells in LAC and carboplatin groups were significantly increased (P <0.05).The IC50 of carboplatin was dropped from 58.08 μmol·L-1 to 18.37 μmol·L-1 .The FCM results showed that with the prolongation of treated time of LAC,the apoptotic rates of SKOV3 cells were increased;compared with carboplatin group and LAC group,the apoptotic rate of cells in LAC and carboplatin group was increased (P <0.05).Conclusion:LAC can inhibit the proliferation of the ovarian cancer SKOV3 cells and induce the apoptosis, and LAC can enhance the inhibitory effect of proliferation of carboplatin on the ovarian cancer SKOV3 cells.

Intervention effect of proteasome inhibitor MG132 in rats with collagen-induced arthritis / 中国免疫学杂志

Objective:To explore the intervention effect of proteasome inhibitor MG132 in rats with collagen-induced arthritis(CIA),which resembles human rheumatoid arthritis(RA).Methods:Forty-eight female SD rats were randomly divided into three groups,including blank control group,CIA model group and MG132-treated group.There were sixteen rats in each group.Rats in CIA model group and MG132-treated model group were injected with type Ⅱ collagen to established CIA rats.21 days after the initial immunization,the rats in the MG132-treated model group were injected subcutaneously with 1 mg/kg MG132 once daily for 2 weeks.42 days after the initial immunization,the change of paw-swelling and the arthritis scores were determined.The synovial pathology examination was performed with HE staining.The 20S proteasome activity in synovial tissue was measured by fluorescence substrate assay.The expression of NF-κB/p65,IκBα in synovial tissue were analyzed by Western blot.Results:Proteasome inhibitor MG132 significantly attenuated the severity of arthritis and histopathological changes in CIA rats.Compared with the blank control group,the 20S proteasome activity was increased significantly in the CIA model group(P<0.05),and decreased after injection of MG132.Compared with CIA rats,the expression of NF-κB/p65 significantly decreased in rats treated with MG132(P<0.01).Compared with the blank control group,the expression of IκBα protein decreased in CIA model group.After injected with MG132,the protein was significantly increased(P<0.01).Conclusion:The proteasome inhibitor MG132 may attenuates the severity of arthritis and histopathological changes in CIA rats.These effects may be mediated through the inhibition of NF-κB activity.

Proteasome Inhibitor MG132 Inhibits Cell Proliferation and Induces Cell Apoptosis in Acute T Lymphoblastic Leukemia Cell Via FOXO3a/Puma Pathway / 中山大学学报(医学科学版)

[Objective]To explore the effect and the possible mechanism of the proteasome inhibitor MG132 on acute T lympho?blastic leukemia cells.[Methods]The influence of different concentrations of MG132 in the viability and proliferation of CCRF-CEM was measured by MTS. Apoptosis rates of CCRF-CEM treated by MG132 were determined by flow cytometry. After being exposed to MG132,the protein levels of FOXO3a in cytoplasm and nucleus were analyzed by Western blotting. qRT-PCR was applied to detect the mRNA of FOXO3a and Puma in cells treated by MG132. Then CCRF-CEM was stably transfected with antisense FOXO3a using Lentivirus infection. We further investigated the effects of MG132 in FOXO3a-shRNA cells and elucidated the mechanisms of FOXO3a and Puma.[Results]MG132 inhibits the proliferation of CCRF-CEM,but has no cytotoxicity in peripheral blood mononu?clear cells(PBMC). Cellular apoptosis was induced in cells treated with MG132. At mRNA level,MG132 had no influence on FOXO3a,but increased the expression of Puma. However,MG132 promoted the expression of both FOXO3a and Puma at protein level. Interestingly,the expression of FOXO3a increased very little in cytoplasm. In FOXO3a-shRNA cells the expression of FOXO3a and Puma decreased at protein level. FOXO3a's knockdown attenuated the proliferation inhibition mediated by MG132.[Conclusion]MG132 inhibits the proliferation and promotes to apoptosis of CCRF-CEM. One of the mechanism is that MG132 inhib? its the degradation of FOXO3a,and then activates FOXO3a/Puma pathway.

MG132 Affects on the Nude Mice Transplanted Tumor Tissues of Ovarian Epithelial Carcinoma and the Relationship with Cisplatin Combination / 实用妇产科杂志

Objective:To investigate the potential value and feasibility of MG132 as a new therapy method for the ovarian cancer and a cisplatin chemotherapy-synergistic agent.Methods:The mode of the nude mice transplanted tumor tissues of ovarian epithelial carcinoma were established,20 nude mice were randomly divided into four groups and were all intrapedtoneal injected,once a day,a total of seven days:①Control group(0.2 ml saline),②MG132 group(2 mg/kg),③Cisplatin group(1 mg/kg),④Combination group[MG132(2 mg/kg) + cisplatin (1 mg/kg)].The weight inhibitory rates of tumors in each group were compared after four weeks.The expressions of Caspase3,Beclin1 in each group were detected by IHC,FIA,western blot and RT-PCR.Results:①The inhibitory rate of tumors in cisplatin group,MG132 group,and combination group was 53.85％,15.38％,88.46％,respectively,the additive effect of cisplatin and MG132 combination therapy was 60.95％.②IHC,FIA,western blot detected that compared to control group,the positive expressions of Beclin1,Caspase3 were increased in cisplatin group,MG132 group,and combination group,among which combination group increased more.③RT-PCR detected that the mRNA relative quantity of Beclin1 in cisplatin group,MG132 group,combination group respectively were higher than that of control group(P＜0.05);and it was higher in combination group than that of cisplatin group and MG132 group(P＜0.05).Conclusions:The growth of nude mice transplanted tumor tissues of ovarian epithelial carcinoma can be inhibited by MG132,and has a synergistic effect for treating ovarian cancer by combination with cisplatin,it is expected to be an effective anti-tumor drug for platinum resistant refractory ovarian cancer.

Resistance mechanism of bortezomib in multiple myeloma / 白血病·淋巴瘤

Bortezomib (BTZ), being the first proteasome inhibitor, has been applied widely in clinic. Through combining with targeting β5 subunit/chymotrypsin-like and inhibiting the activity of proteasome reversibly, BTZ manages to inhibit intracellular degradation of protein, thus inducing apoptosis of myeloma cells. Since 2000, when BTZ was approved by Food and Drug Administration (FDA) for treatment of multiple myeloma (MM), both response rates and long-term survival time of these patients have been improved significantly. However, most patients will inevitably end up with relapse or drug resistance due to its high heterogeneity. Thus, it is of great necessity to explore the mechanism as well as overcome BTZ resistance. This review aims to summarize the current researches available on mechanisms of BTZ resistance in MM.

Recent progress of multiple myeloma: reports from the 57th American Society of Hematology annual meeting / 白血病·淋巴瘤

The diagnosis and treatment of multiple myeloma (MM) have make remarkable progress, which were reviewed in the 57th American Society of Hematology (ASH) annual meeting. In this annual meeting, the effects of advanced proteasome inhibitor (PI), antibody, checkpoint blockade, immunomodulatory agent (IMiD), histone deacetylase (HDACI) and chimeric antigen receptor T-cell (CAR-T), and new diagnostic technologies were reported. The real point is to apply the best available diagnosis and therapy at this meeting. At present, regardless of advances, all of randomized clinical trials push to combined agents, and combined with hematopoietic stem cell transplantation, efficacy will be improved in further. So some professors also refered to 2015 year as 'the advance year of MM'.

Recent progress in multiple myeloma / 白血病·淋巴瘤

The treatments of multiple myeloma (MM) have been made remarkable progress in recent years,and especially in 2015,FDA approved a number of new drugs for treatment of relapsed and refractory MM.At the 21th European Hematology Association Annual Meeting,the issue of MM has received a lot of attention.The recent progress of MM in this conference will be briefly introduced in this review.

Mechanism of resistance to proteasome inhibitor bortezomib in multiple myeloma / 白血病·淋巴瘤

Multiple myeloma (MM) is a malignant plasma cell disease which occured predominantly in the elderly.In recent years,due to the application of small molecular proteasome inhibitor and immunomodulator,MM has become a chronic disease with good response to new treatments rather than a deadly disease that is lack of effective treatments.However,the occurrence of drug resistance makes MM less likely to be cured,which is one of the biggest challenges in MM clinical treatment.This article will review the mechanisms of acquired resistance to bortezomib in MM,including target genes modification,bypass signaling and so forth.

Bortezomib in newly diagnosed patients with multiple myeloma: A retrospective analysis from a tertiary care center in India.

INTRODUCTION: Bortezomib is a novel proteasome inhibitor in myeloma. There is a paucity of data from India regarding the efficacy and tolerance to bortezomib. MATERIALS AND METHODS: All patients with newly diagnosed multiple myeloma from January 2008 to December 2011 treated with bortezomib as the first‑line therapy were studied in a retrospective analysis. The primary end point was the overall rate of response. Secondary end points were the progression free survival (PFS), reversibility of renal compromise and safety of bortezomib. RESULTS: Our study included 41 patients with newly diagnosed myeloma. The overall response to bortezomib was 88.5% (complete response [CR] 31.4%, very good partial response 34.2%, partial response [PR] 22.8%). A renal response (CR renal, PR renal or Minimal Response renal combined) was documented 96.2% patients with initial renal impairment. The median time to the first renal response was 21 days. 17 patients (41.4%) had severe toxicity (Grade 3 and 4). Bortezomib induced peripheral neuropathy (BIPN) was the most common toxicity seen (53.6%) and the most common cause for discontinuation of therapy. At a median follow‑up of 9 months, median PFS was not reached. DISCUSSION: The results obtained in our study are comparable with those of established studies on bortezomib. Our patient population has similar responses and renal reversibility patterns. However, they are at an increased susceptibility to BIPN, leading to discontinuation of therapy. CONCLUSION: Bortezomib as first‑line therapy has a good efficacy and safety.

The Effect of Bortezomib on Expression of Inflammatory Cytokines and Survival in a Murine Sepsis Model Induced by Cecal Ligation and Puncture

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.