-
PLoS Pathogens Dec 2021Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all... (Review)
Review
Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all 3 kingdoms. Pharmacological inhibition of proteasomes is detrimental to cell viability. Proteasome inhibitor rugs revolutionize the treatment of multiple myeloma. Proteasomes in pathogenic microbes such as Mycobacterium tuberculosis (Mtb), Plasmodium falciparum (Pf), and other parasites and worms have been validated as therapeutic targets. Starting with Mtb proteasome, efforts in developing inhibitors selective for microbial proteasomes have made great progress lately. In this review, we describe the strategies and pharmacophores that have been used in developing proteasome inhibitors with potency and selectivity that spare human proteasomes and highlight the development of clinical proteasome inhibitor candidates for treatment of leishmaniasis and Chagas disease. Finally, we discuss the future challenges and therapeutical potentials of the microbial proteasome inhibitors.
Topics: Animals; Chagas Disease; Humans; Leishmaniasis; Mycobacterium tuberculosis; Plasmodium falciparum; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 34882737
DOI: 10.1371/journal.ppat.1010058 -
Nature Communications Nov 2022Serum monoclonal immunoglobulin (Ig) is the main diagnostic factor for patients with multiple myeloma (MM), however its prognostic potential remains unclear. On a large...
Serum monoclonal immunoglobulin (Ig) is the main diagnostic factor for patients with multiple myeloma (MM), however its prognostic potential remains unclear. On a large MM patient cohort (n = 4146), we observe no correlation between serum Ig levels and patient survival, while amount of intracellular Ig has a strong predictive effect. Focused CRISPR screen, transcriptional and proteomic analysis identify deubiquitinase OTUD1 as a critical mediator of Ig synthesis, proteasome inhibitor sensitivity and tumor burden in MM. Mechanistically, OTUD1 deubiquitinates peroxiredoxin 4 (PRDX4), protecting it from endoplasmic reticulum (ER)-associated degradation. In turn, PRDX4 facilitates Ig production which coincides with the accumulation of unfolded proteins and higher ER stress. The elevated load on proteasome ultimately potentiates myeloma response to proteasome inhibitors providing a window for a rational therapy. Collectively, our findings support the significance of the Ig production machinery as a biomarker and target in the combinatory treatment of MM patients.
Topics: Humans; Proteasome Inhibitors; Multiple Myeloma; Bortezomib; Proteomics; Apoptosis; Proteasome Endopeptidase Complex; Immunoglobulins; Deubiquitinating Enzymes; Ubiquitin-Specific Proteases
PubMed: 36357400
DOI: 10.1038/s41467-022-34654-2 -
Transplantation and Cellular Therapy Nov 2021Graft-versus-host disease (GVHD) is a frequent complication in the first year after allogeneic stem cell transplantation (allo-HCT). Recipients of reduced-intensity (RI)...
Oral Proteasome Inhibitor Ixazomib for Switch-Maintenance Prophylaxis of Recurrent or Late Acute and Chronic Graft-versus-Host Disease after Day 100 in Allogeneic Stem Cell Transplantation.
Graft-versus-host disease (GVHD) is a frequent complication in the first year after allogeneic stem cell transplantation (allo-HCT). Recipients of reduced-intensity (RI) or nonmyeloablative (NMA) conditioning combined with calcineurin inhibitor (CNI)-based GVHD prophylaxis frequently develop GVHD in the context of immunosuppression taper. Ixazomib is an oral proteasome inhibitor with a wide safety profile that has demonstrated immunomodulatory properties, inhibition of pro-inflammatory cytokines, and anti-tumor activity. We hypothesized that switch-maintenance GVHD prophylaxis using ixazomib would facilitate CNI taper without increased GVHD frequency and severity while maintaining graft-versus-tumor (GVT) effect and an acceptable safety profile. We conducted an open-label, prospective, single-center pilot study in patients with hematologic malignancies who received an RI or NMA conditioning and CNI-based GVHD prophylaxis that were within day 100 to 150 after HCT (n = 18). Patients were treated with ixazomib once weekly on a 28-day cycle (3 weeks on, 1 week off). Treatment was safe; most adverse events were grade 1 or 2, with cytopenia and elevation in transaminases the most common. Five patients were removed from the study because of toxicity or side effects. Only 5 of 18 patients developed GVHD during the study, and its severity was driven by acute manifestations while chronic involvement was mild. The cumulative incidence of grade II-IV acute and chronic GVHD at 1-year after HCT was 33% (95% confidence interval [CI], 13-55). No patients died during the study, and only 1 had malignant relapse. An additional patient relapsed after completion of the study but within 1 year after HCT. The probability of progression-free survival and GVHD-free/relapse-free survival (composite endpoint) at 1 year were 89% (95% CI, 75-100) and 78% (95% CI, 61-100), respectively. Immune reconstitution analysis showed a rapid and sustained recovery in T-cell subpopulations and B cell reconstitution, and vaccine response in a subset of patients demonstrated continuing or de novo positive protective antibody titers. This study demonstrated low incidence of recurrent and late acute and chronic GVHD within 1 year after HCT possible associated with switch-maintenance GVHD prophylaxis using ixazomib. This approach allowed for CNI taper while preserving GVT effect, without aggravating GVHD. Our findings support further development of this approach and provide a proof-of-concept for switch-maintenance GVHD prophylaxis.
Topics: Boron Compounds; Glycine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Neoplasm Recurrence, Local; Pilot Projects; Prospective Studies; Proteasome Inhibitors
PubMed: 34029766
DOI: 10.1016/j.jtct.2021.05.008 -
Cell Chemical Biology Jun 2017While proteasome inhibitors are now well-established research tools and chemotherapeutics, proteasome activators are much less explored. In this issue of Cell Chemical...
While proteasome inhibitors are now well-established research tools and chemotherapeutics, proteasome activators are much less explored. In this issue of Cell Chemical Biology, in a study from the groups of Berkers and Ovaa (Leestemaker et al., 2017), a chemical screen was used to identify a p38 MAPK inhibitor as a proteasome activator. This compound furthermore enhanced clearance of protein aggregates, thereby implicating alternative chemotherapeutic options for treating neurodegenerative diseases.
Topics: Enzyme Activation; Proteasome Endopeptidase Complex; Proteasome Inhibitors; p38 Mitogen-Activated Protein Kinases
PubMed: 28644955
DOI: 10.1016/j.chembiol.2017.06.005 -
Seminars in Oncology Dec 2017Since 2003, the US Food and Drug Administration approval of bortezomib, a proteasome inhibitor, has changed the management of hematologic malignancies and dramatically... (Review)
Review
Since 2003, the US Food and Drug Administration approval of bortezomib, a proteasome inhibitor, has changed the management of hematologic malignancies and dramatically improved outcomes for patients with multiple myeloma and mantle cell lymphoma. Since that time, two additional proteasome inhibitors (carfilzomib and ixazomib) have been approved, with other agents and combinations currently under investigation. Proteasomes degrade ubiquitinated proteins or substrates through the ubiquitin-proteasome pathway, a pathway that is utilized in multiple myeloma because of the high protein turnover with immunoglobulin production. Proteasome inhibitors exploit dependence on this pathway, halting protein degradation that ultimately results in apoptosis and cell death. Here we will discuss the structure of the proteasome and the mechanisms of action for proteasome inhibitors to further understand their role in hematologic malignancies.
Topics: Antineoplastic Agents; Boron Compounds; Bortezomib; Glycine; Hematologic Neoplasms; Humans; Lymphoma, Mantle-Cell; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Structure-Activity Relationship
PubMed: 29935898
DOI: 10.1053/j.seminoncol.2018.01.004 -
Blood Advances Feb 2023Proteasome inhibition is a highly effective treatment for multiple myeloma (MM). However, virtually all patients develop proteasome inhibitor resistance, which is...
Proteasome inhibition is a highly effective treatment for multiple myeloma (MM). However, virtually all patients develop proteasome inhibitor resistance, which is associated with a poor prognosis. Hyperactive small ubiquitin-like modifier (SUMO) signaling is involved in both cancer pathogenesis and cancer progression. A state of increased SUMOylation has been associated with aggressive cancer biology. We found that relapsed/refractory MM is characterized by a SUMO-high state, and high expression of the SUMO E1-activating enzyme (SAE1/UBA2) is associated with poor overall survival. Consistently, continuous treatment of MM cell lines with carfilzomib (CFZ) enhanced SUMO pathway activity. Treatment of MM cell lines with the SUMO E1-activating enzyme inhibitor subasumstat (TAK-981) showed synergy with CFZ in both CFZ-sensitive and CFZ-resistant MM cell lines, irrespective of the TP53 state. Combination therapy was effective in primary MM cells and in 2 murine MM xenograft models. Mechanistically, combination treatment with subasumstat and CFZ enhanced genotoxic and proteotoxic stress, and induced apoptosis was associated with activity of the prolyl isomerase PIN1. In summary, our findings reveal activated SUMOylation as a therapeutic target in MM and point to combined SUMO/proteasome inhibition as a novel and potent strategy for the treatment of proteasome inhibitor-resistant MM.
Topics: Humans; Animals; Mice; Proteasome Inhibitors; Multiple Myeloma; Sumoylation; Proteasome Endopeptidase Complex; Apoptosis; Ubiquitin-Activating Enzymes; NIMA-Interacting Peptidylprolyl Isomerase
PubMed: 35917568
DOI: 10.1182/bloodadvances.2022007875 -
Translational Research : the Journal of... Aug 2018Over 2 decades ago, the proteasome was considered a risky or even untenable therapeutic target. Today, proteasome inhibitors are a mainstay in the treatment of multiple... (Review)
Review
Over 2 decades ago, the proteasome was considered a risky or even untenable therapeutic target. Today, proteasome inhibitors are a mainstay in the treatment of multiple myeloma (MM) and have sales in excess of 3 billion US dollars annually. More importantly, the availability of proteasome inhibitors has greatly improved the survival and quality of life for patients with MM. Despite the remarkable success of proteasome inhibitor therapies to date, the potential for improvement remains, and the development and optimal use of proteasome inhibitors as anticancer agents continues to be an active area of research. In this review, we briefly discuss the features and limitations of the 3 proteasome inhibitor drugs currently used in the clinic and provide an update on current efforts to develop next-generation proteasome inhibitors with the potential to overcome the limitations of existing proteasome inhibitor drugs.
Topics: Antineoplastic Agents; Boron Compounds; Bortezomib; Drug Resistance, Neoplasm; Glycine; Humans; Neoplasms; Oligopeptides; Proteasome Inhibitors
PubMed: 29654740
DOI: 10.1016/j.trsl.2018.03.002 -
Cell Chemical Biology Aug 2022Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated...
Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated genetic co-dependencies. We identified heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma cells overcoming PI-induced stress. We therefore explored allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. JG compounds exhibited increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Shotgun and pulsed SILAC mass spectrometry demonstrated that JGs unexpectedly impact myeloma proteostasis by destabilizing the 55S mitoribosome. Our data suggest JGs have the most pronounced anti-myeloma effect not through inhibiting cytosolic HSP70 proteins but instead through mitochondrial-localized HSP70, HSPA9/mortalin. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.
Topics: Antineoplastic Agents; Cell Line, Tumor; HSP70 Heat-Shock Proteins; Humans; Multiple Myeloma; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteostasis
PubMed: 35853457
DOI: 10.1016/j.chembiol.2022.06.010 -
Bioscience Reports Feb 2022Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug resistance and high mortality rates....
Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug resistance and high mortality rates. To counter this global problem, novel proteasome-based therapies are being developed. In the current study, we extensively characterize TIR-199, a syrbactin-class proteasome inhibitor derived from a plant virulence factor of bacterium Pseudomonas syringae pv syringae. We report that TIR-199 is a potent constitutive and immunoproteasome inhibitor, capable of inducing cell death in multiple myeloma, triple-negative breast cancer, (TNBC) and non-small cell lung cancer lines. TIR-199 also effectively inhibits the proteasome in primary myeloma cells of patients, and bypasses the PSMB5 A49T+A50V bortezomib-resistant mutant. TIR-199 treatment leads to accumulation of canonical proteasome substrates in cells, it is specific, and does not inhibit 50 other enzymes tested in vitro. The drug exhibits synergistic cytotoxicity in combination with proteasome-activating kinase DYRK2 inhibitor LDN192960. Furthermore, low-doses of TIR-199 exhibits in vivo activity by delaying myeloma-mediated bone degeneration in a mouse xenograft model. Together, our data indicates that proteasome inhibitor TIR-199 could indeed be a promising next-generation drug within the repertoire of proteasome-based therapeutics.
Topics: Amides; Animals; Antineoplastic Agents; Azoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mice; Multiple Myeloma; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 35088066
DOI: 10.1042/BSR20212721 -
International Journal of Molecular... Dec 2017The treatment of organ failure on patients requires the transplantation of functional organs, from donors. Over time, the methodology of transplantation was improved by... (Review)
Review
The treatment of organ failure on patients requires the transplantation of functional organs, from donors. Over time, the methodology of transplantation was improved by the development of organ preservation solutions. The storage of organs in preservation solutions is followed by the ischemia of the organ, resulting in a shortage of oxygen and nutrients, which damage the tissues. When the organ is ready for the transplantation, the reperfusion of the organ induces an increase of the oxidative stress, endoplasmic reticulum stress, and inflammation which causes tissue damage, resulting in a decrease of the transplantation success. However, the addition of proteasome inhibitor in the preservation solution alleviated the injuries due to the ischemia-reperfusion process. The proteasome is a protein structure involved in the regulation the inflammation and the clearance of damaged proteins. The goal of this review is to summarize the role of the proteasome and pharmacological compounds that regulate the proteasome in protecting the organs from the ischemia-reperfusion injury.
Topics: Endoplasmic Reticulum Stress; Food; Humans; Inflammation; Organ Preservation; Organ Transplantation; Oxidative Stress; Oxygen; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Reperfusion Injury
PubMed: 29301204
DOI: 10.3390/ijms19010106