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Cells Jun 2021The ubiquitin-proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential... (Review)
Review
The ubiquitin-proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.
Topics: Hematologic Neoplasms; Hematopoiesis; Humans; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Signal Transduction
PubMed: 34206607
DOI: 10.3390/cells10071577 -
BMC Ophthalmology May 2019The purpose of this case series was to further characterize proteasome inhibitor associated chalazia and blepharitis, to investigate outcomes of different management...
BACKGROUND
The purpose of this case series was to further characterize proteasome inhibitor associated chalazia and blepharitis, to investigate outcomes of different management strategies, and to propose a treatment algorithm for eyelid complications in this patient population.
METHODS
This retrospective case series included sixteen patients found to have chalazia and/or blepharitis while receiving proteasome inhibitors for plasma cell disorders at Mount Sinai Hospital in New York, NY from January 2010 through January 2017. Main outcomes were complete resolution of eyelid complications and time to resolution. Student's t-test was used to compare average values and Fisher's exact test was used to compare proportions.
RESULTS
Fourteen patients had chalazia and 10 had blepharitis. Chalazia averaged 5.4 mm, and 11 patients with chalazia experienced two or more lesions. Median follow-up time was 17 months. Average time from bortezomib exposure to onset of first eyelid complication was 3.4 months. Chalazia episodes were more likely to completely resolve than blepharitis episodes (p = 0.03). Ocular therapy alone was trialed for an average of 1.8 months before proceeding to bortezomib omission. Average time to eyelid complication resolution using ocular therapy alone was 1.8 months versus 3.1 months after bortezomib omission. In this series, the combination of ocular therapy and bortezomib omission led to complete resolution of eyelid complications more often than ocular therapy alone.
CONCLUSION
Proteasome inhibitor associated eyelid complications were identified in sixteen patients with plasma cell disorders. Eyelid complications may be treated with a 2-month trial of conservative ocular therapies alone, followed by continuation of ocular therapy in combination with bortezomib omission if eyelid signs persist.
Topics: Adult; Aged; Aged, 80 and over; Blepharitis; Bortezomib; Chalazion; Female; Humans; Male; Middle Aged; Neoplasms, Plasma Cell; Proteasome Inhibitors; Retrospective Studies
PubMed: 31088416
DOI: 10.1186/s12886-019-1118-x -
Molecules (Basel, Switzerland) Feb 2023Although proteasome inhibitors have emerged as the therapeutic backbone of multiple myeloma treatment, patients often relapse and become drug refractory. The combination...
Although proteasome inhibitors have emerged as the therapeutic backbone of multiple myeloma treatment, patients often relapse and become drug refractory. The combination between proteasome and histone deacetylase inhibitors has shown to be more efficient compared to monotherapy by enhancing the anti-myeloma activity and improving the patient's lifetime expectancy. Hybrid molecules, combining two drugs/pharmacophores in a single molecular entity, offer improved effectiveness by modulating more than one target and circumventing differences in the pharmacokinetic and pharmacodynamic profiles, which are the main disadvantages of combination therapy. Therefore, eleven histone deacetylase-proteasome inhibitor hybrids were synthesized, combining pharmacophores of entinostat and bortezomib. Compound displayed the strongest antiproliferative activity with an IC value of 9.5 nM in the multiple myeloma cells RPMI 8226, 157.7 nM in the same cell line resistant to bortezomib, and 13.1 nM in a 3D spheroid model containing multiple myeloma and mesenchymal stem cells. Moreover, the compound inhibited 33% of histone deacetylase activity when RPMI 8226 cells were treated for 8 h at 10 µM. It also inhibited the proteasome activity with an IC value of 23.6 nM.
Topics: Humans; Bortezomib; Multiple Myeloma; Antineoplastic Agents; Proteasome Endopeptidase Complex; Boronic Acids; Cell Line, Tumor; Neoplasm Recurrence, Local; Proteasome Inhibitors; Histone Deacetylase Inhibitors; Histone Deacetylases; Drug Resistance, Neoplasm
PubMed: 36771118
DOI: 10.3390/molecules28031456 -
Proceedings of the National Academy of... Mar 2023We have previously shown that proteasome inhibitor bortezomib stabilizes p53 in stem and progenitor cells within gastrointestinal tissues. Here, we characterize the...
We have previously shown that proteasome inhibitor bortezomib stabilizes p53 in stem and progenitor cells within gastrointestinal tissues. Here, we characterize the effect of bortezomib treatment on primary and secondary lymphoid tissues in mice. We find that bortezomib stabilizes p53 in significant fractions of hematopoietic stem and progenitor cells in the bone marrow, including common lymphoid and myeloid progenitors, granulocyte-monocyte progenitors, and dendritic cell progenitors. The stabilization of p53 is also observed in multipotent progenitors and hematopoietic stem cells, albeit at lower frequencies. In the thymus, bortezomib stabilizes p53 in CD4CD8 T cells. Although there is less p53 stabilization in secondary lymphoid organs, cells in the germinal center of the spleen and Peyer's patch accumulate p53 in response to bortezomib. Bortezomib induces the upregulation of p53 target genes and p53 dependent/independent apoptosis in the bone marrow and thymus, suggesting that cells in these organs are robustly affected by proteasome inhibition. Comparative analysis of cell percentages in the bone marrow indicates expanded stem and multipotent progenitor pools in p53R172H mutant mice compared with p53 wild-type mice, suggesting a critical role for p53 in regulating the development and maturation of hematopoietic cells in the bone marrow. We propose that progenitors along the hematopoietic differentiation pathway express relatively high levels of p53 protein, which under steady-state conditions is constantly degraded by Mdm2 E3 ligase; however, these cells rapidly respond to stress to regulate stem cell renewal and consequently maintain the genomic integrity of hematopoietic stem/progenitor cell populations.
Topics: Mice; Animals; Bortezomib; Tumor Suppressor Protein p53; Proteasome Inhibitors; Hematopoietic Stem Cells; Myeloid Progenitor Cells; Mice, Inbred C57BL
PubMed: 36940336
DOI: 10.1073/pnas.2219978120 -
Biomolecules Dec 2021Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby... (Review)
Review
Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in recent years, different BTZ-based drug delivery systems have been evaluated. In this review, we firstly discussed the functions of proteasome inhibitors and their mechanisms of action. Secondly, the properties of BTZ, as well as recent advances in both clinical and preclinical research, were reviewed. Finally, progress in research regarding BTZ-based nanoformulations was summarized.
Topics: Adult; Antineoplastic Agents; Bortezomib; Cell Line, Tumor; Drug Delivery Systems; Humans; Multiple Myeloma; Proteasome Inhibitors
PubMed: 35053199
DOI: 10.3390/biom12010051 -
Cell Reports. Medicine Sep 2022Although the MAPK pathway is aberrantly activated in triple-negative breast cancers (TNBCs), the clinical outcome of MEK-targeted therapy is still poor. Through a...
Although the MAPK pathway is aberrantly activated in triple-negative breast cancers (TNBCs), the clinical outcome of MEK-targeted therapy is still poor. Through a genome-wide CRISPR-Cas9 library screening, we find that inhibition of PSMG2 sensitizes TNBC cells BT549 and MB468 to the MEK inhibitor AZD6244. Mechanistically, PSMG2 knockdown impairs proteasome function, which in turn activates autophagy-mediated PDPK1 degradation. The PDPK1 degradation significantly enhances AZD6244-induced tumor cell growth inhibition by interrupting the negative feedback signals toward the AKT pathway. Consistently, co-targeting proteasomes and MEK with inhibitors synergistically suppresses tumor cell growth. The autophagy inhibitor chloroquine partially relieves the PDPK1 degradation and reverses the growth inhibition induced by combinatorial inhibition of MEK and proteasome. The combination regimen with the proteasome inhibitor MG132 plus AZD6244 synergistically inhibits tumor growth in a 4T1 xenograft mouse model. In summary, our study not only unravels the mechanism of MEK inhibitor resistance but also provides a combinatorial therapeutic strategy for TNBC in clinics.
Topics: 3-Phosphoinositide-Dependent Protein Kinases; Animals; Autophagy; Cell Line, Tumor; Chaperonins; Chloroquine; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proto-Oncogene Proteins c-akt; Triple Negative Breast Neoplasms
PubMed: 36099919
DOI: 10.1016/j.xcrm.2022.100741 -
International Journal of Molecular... Aug 2021Bortezomib (BTZ) has demonstrated its efficacy in several hematological disorders and has been associated with thrombocytopenia. There is controversy about the effect of...
Bortezomib (BTZ) has demonstrated its efficacy in several hematological disorders and has been associated with thrombocytopenia. There is controversy about the effect of BTZ on human platelets, so we set out to determine its effect on various types of platelet samples. Human platelets were investigated in platelet-rich plasma (PRP) and as gel-filtered platelets (GFPs). Mitochondrial inner membrane potential depolarization and phosphatidylserine (PS) and P-selectin expression levels were studied by flow cytometry, while thrombin generation was measured by a fluorescent method. In PRP, BTZ caused negligible PS expression after 60 min of treatment. However, in GFPs, PS expression was dose- and time-dependently increased in the BTZ-treated groups, as was P-selectin. The percentage of depolarized cells was also higher after BTZ pretreatment at both time points. Peak thrombin and velocity index increased significantly even with the lowest BTZ concentration ( = 0.0019; = 0.0032) whereas time to peak and start tail parameters decreased ( = 0.0007; = 0.0034). The difference between PRP and GFP results can be attributed to the presence of plasma proteins in PRP, as the PS-stimulating effect of BTZ could be attenuated by supplementing GFPs with purified human albumin. Overall, BTZ induces a procoagulant platelet phenotype in an experimental setting devoid of plasma proteins.
Topics: Antineoplastic Agents; Apoptosis; Blood Coagulation; Blood Platelets; Bortezomib; Humans; P-Selectin; Platelet Activation; Proteasome Inhibitors
PubMed: 34445660
DOI: 10.3390/ijms22168955 -
International Journal of Radiation... Apr 2024Radiation therapy is a primary treatment for cancer, but radioresistance remains a significant challenge in improving efficacy and reducing toxicity. Accumulating... (Review)
Review
Radiation therapy is a primary treatment for cancer, but radioresistance remains a significant challenge in improving efficacy and reducing toxicity. Accumulating evidence suggests that deubiquitinases (DUBs) play a crucial role in regulating cell sensitivity to ionizing radiation. Traditional small-molecule DUB inhibitors have demonstrated radiosensitization effects, and novel deubiquitinase-targeting chimeras (DUBTACs) provide a promising strategy for radiosensitizer development by harnessing the ubiquitin-proteasome system. This review highlights the mechanisms by which DUBs regulate radiosensitivity, including DNA damage repair, the cell cycle, cell death, and hypoxia. Progress on DUB inhibitors and DUBTACs is summarized, and their potential radiosensitization effects are discussed. Developing drugs targeting DUBs appears to be a promising alternative approach to overcoming radioresistance, warranting further research into their mechanisms.
Topics: Humans; Antineoplastic Agents; Proteasome Inhibitors; Neoplasms; Deubiquitinating Enzymes; Radiation Tolerance
PubMed: 38092257
DOI: 10.1016/j.ijrobp.2023.12.003 -
British Journal of Haematology Jul 2018The number of novel therapies for the treatment of myeloma is rapidly increasing, as are the clinical trials evaluating them in combination with other novel and... (Review)
Review
The number of novel therapies for the treatment of myeloma is rapidly increasing, as are the clinical trials evaluating them in combination with other novel and established therapies. Proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are the most well known and studied classes of novel agents targeting myeloma, with histone deacetylase inhibitors, nuclear export inhibitors and several other approaches also being actively investigated. However, in parallel with the development and clinical use of these novel myeloma therapies is the emergence of novel mechanisms of resistance, many of which remain elusive, particularly for more recently developed agents. Whilst resistance mechanisms have been best studied for proteasome inhibitors, particularly bortezomib, class effects do not universally apply to all class members, and within-class differences in efficacy, toxicity and resistance mechanisms have been observed. Although immunomodulatory agents share the common cellular target cereblon and thus resistance patterns relate to cereblon expression, the unique cell surface antigens to which monoclonal antibodies are directed means these agents frequently exhibit unique within-class differences in clinical efficacy and resistance patterns. This review describes the major classes of novel therapies for myeloma, highlights the major clinical trials within each class and discusses known resistance mechanisms.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Immunologic Factors; Multiple Myeloma; Mutation; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Ubiquitin
PubMed: 29676460
DOI: 10.1111/bjh.15210 -
Chemical Biology & Drug Design Nov 2015The ubiquitin-proteasome system (UPS) is increasingly recognized as a therapeutic target for the development of anticancer therapies. The success of the 20S proteasome...
The ubiquitin-proteasome system (UPS) is increasingly recognized as a therapeutic target for the development of anticancer therapies. The success of the 20S proteasome core particle (20S CP) inhibitor bortezomib in the clinical management of multiple myeloma has raised the possibility of identifying other UPS components for therapeutic intervention. We previously identified the small molecule b-AP15 as an inhibitor of 19S proteasome deubiquitinase (DUB) activity. Building upon our previous data, we performed a structure-activity relationship (SAR) study on b-AP15 and identified VLX1570 as an analog with promising properties, including enhanced potency and improved solubility in aqueous solution. In silico modeling was consistent with interaction of VLX1570 with key cysteine residues located at the active sites of the proteasome DUBs USP14 and UCHL5. VLX1570 was found to inhibit proteasome deubiquitinase activity in vitro in a manner consistent with competitive inhibition. Furthermore, using active-site-directed probes, VLX1570 also inhibited proteasome DUB activity in exposed cells. Importantly, VLX1570 did not show inhibitory activity on a panel of recombinant non-proteasome DUBs, on recombinant kinases, or on caspase-3 activity, suggesting that VLX1570 is not an overtly reactive general enzyme inhibitor. Taken together, our data shows the chemical and biological properties of VLX1570 as an optimized proteasome DUB inhibitor.
Topics: Animals; Cell Line, Tumor; Chalcones; Humans; Male; Molecular Docking Simulation; Proteasome Inhibitors; Rats, Sprague-Dawley; Structure-Activity Relationship; Ubiquitin-Specific Proteases
PubMed: 25854145
DOI: 10.1111/cbdd.12571