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Panminerva Medica Dec 2020Proteasome inhibitors (PIs) represent a recently developed drug class that inhibit the ubiquitin-proteasome system, thus interfering with the intracellular machinery who... (Review)
Review
Proteasome inhibitors (PIs) represent a recently developed drug class that inhibit the ubiquitin-proteasome system, thus interfering with the intracellular machinery who has the duty of misfolded proteins disposal. Myeloma plasma cells are structurally aimed at the production of large quantities of immunoglobulins. This explains their vulnerability to any perturbation of intracellular protein homeostasis. Bortezomib is the first-in-class PI and nowadays, in combination with other compounds, is the cornerstone of multiple myeloma (MM) treatment in several settings. Bortezomib has several attractive features for its inclusion in the induction phase of therapy: high efficacy, rapid cytoreduction, absence of nephrotoxicity, fast reduction of plasmacytomas, and fast pain control. However, the safety profile of bortezomib is characterized by a not negligible peripheral neuropathy. Newer PIs, such as carfilzomib and ixazomib, have been developed and each offers specific advantages. Carfilzomib is extremely efficient in proteasome inhibition. This results in high efficacy but suffers from a significant cardiotoxicity. Ixazomib is the first oral PI with a proteasome inhibition profile similar to bortezomib, with lower neurotoxicity. PIs mechanism of action is complementary with other drug classes, and this explains the synergism between PIs and other drugs, in particular steroids and immunomodulators. PIs are frequently used in doublets and triplets. Also, they can be associated with anti-CD38 monoclonal antibodies. This review summarizes the principal biological and clinical features of PIs in the MM treatment.
Topics: Animals; Antineoplastic Agents; Humans; Multiple Myeloma; Proteasome Inhibitors; Treatment Outcome
PubMed: 32957744
DOI: 10.23736/S0031-0808.20.04148-8 -
Biomolecules May 2022The anti-diabetic drug metformin is currently tested for the treatment of hematological and solid cancers. Proteasome inhibitors, e.g., Bortezomib, are approved for the...
The anti-diabetic drug metformin is currently tested for the treatment of hematological and solid cancers. Proteasome inhibitors, e.g., Bortezomib, are approved for the treatment of multiple myeloma and mantle cell lymphoma but are also studied for lung cancer therapy. We here analyzed the interaction of the two drugs in two cell lines, namely the mantle cell lymphoma Jeko-1 and the non-small-cell lung cancer (NSCLC) H1299 cells, using proliferation and survival assays, native-gel analysis for proteasome activity and assembly, and expression analysis of proteasome assembly factors. Our results demonstrate that metformin treatment induces resistance of cancer cells to the proteasome inhibitor Bortezomib by impairing the activity and assembly of the 26S proteasome complexes. These effects of metformin on proteasome inhibitor sensitivity in cancer cells are of potential relevance for patients that receive proteasome inhibitor therapy.
Topics: Adult; Antineoplastic Agents; Antiviral Agents; Boronic Acids; Bortezomib; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Lymphoma, Mantle-Cell; Metformin; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines
PubMed: 35740881
DOI: 10.3390/biom12060756 -
International Journal of Molecular... May 2020The COVID-19 global pandemic is caused by SARS-CoV-2, and represents an urgent medical and social issue. Unfortunately, there is still not a single proven effective drug... (Review)
Review
The COVID-19 global pandemic is caused by SARS-CoV-2, and represents an urgent medical and social issue. Unfortunately, there is still not a single proven effective drug available, and therefore, current therapeutic guidelines recommend supportive care including oxygen administration and treatment with antibiotics. Recently, patients have been also treated with off-label therapies which comprise antiretrovirals, anti-inflammatory compounds, antiparasitic agents and plasma from convalescent patients, all with controversial results. The ubiquitin-proteasome system (UPS) is important for the maintenance of cellular homeostasis, and plays a pivotal role in viral replication processes. In this review, we discuss several aspects of the UPS and the effects of its inhibition with particular regard to the life cycle of the coronaviruses (CoVs). In fact, proteasome inhibition by various chemical compounds, such as MG132, epoxomycin and bortezomib, may reduce the virus entry into the eucariotic cell, the synthesis of RNA, and the subsequent protein expression necessary for CoVs. Importantly, since UPS inhibitors reduce the cytokine storm associated with various inflammatory conditions, it is reasonable to assume that they might be repurposed for SARS-CoV-2, thus providing an additional tool to counteract both virus replication as well as its most deleterious consequences triggered by abnormal immunological response.
Topics: Antibodies, Monoclonal; Betacoronavirus; COVID-19; Coronavirus Infections; Endoplasmic Reticulum Stress; Humans; Oligopeptides; Pandemics; Pneumonia, Viral; Proteasome Inhibitors; SARS-CoV-2
PubMed: 32443911
DOI: 10.3390/ijms21103622 -
Targeted Oncology Sep 2023Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have previously...
BACKGROUND
Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have previously received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.
OBJECTIVE
We report the population pharmacokinetics of teclistamab administered intravenously and subcutaneously (SC) and exposure-response relationships from the phase I/II, first-in-human, open-label, multicenter MajesTEC-1 study.
METHODS
Phase I of MajesTEC-1 consisted of dose escalation and expansion at the recommended phase II dose (RP2D; 1.5 mg/kg SC weekly, preceded by step-up doses of 0.06 and 0.3 mg/kg); phase II investigated the efficacy of teclistamab RP2D in patients with RRMM. Population pharmacokinetics and the impact of covariates on teclistamab systemic exposure were assessed using a 2-compartment model with first-order absorption for SC and parallel time-independent and time-dependent elimination pathways. Exposure-response analyses were conducted, including overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and the incidence of grade ≥ 3 anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and infection.
RESULTS
In total, 4840 measurable serum concentration samples from 338 pharmacokinetics-evaluable patients who received teclistamab were analyzed. The typical population value of time-independent and time-dependent clearance were 0.449 L/day and 0.547 L/day, respectively. The time-dependent clearance decreased rapidly to < 10% after 8 weeks of teclistamab treatment. Patients who discontinue teclistamab after the 13th dose are expected to have a 50% reduction from C in teclistamab concentration at a median (5th to 95th percentile) time of 15 days (7-33 days) after T and a 97% reduction from C in teclistamab concentration at a median time of 69 days (32-163 days) after T. Body weight, multiple myeloma type (immunoglobulin G vs non-immunoglobulin G), and International Staging System (ISS) stage (II vs I and III vs I) were statistically significant covariates on teclistamab pharmacokinetics; however, these covariates had no clinically relevant effect on the efficacy of teclistamab at the RP2D. Across all doses, ORR approached a plateau at the concentration range associated with RP2D, and in patients who received the RP2D, a flat exposure-response curve was observed. No apparent relationship was observed between DoR, PFS, OS, and the incidence of grade ≥3 adverse events across the predicted exposure quartiles.
CONCLUSION
Body weight, myeloma type, and ISS stage impacted systemic teclistamab exposure without any clinically relevant effect on efficacy. The exposure-response analyses for ORR showed a positive trend with increasing teclistamab systemic exposure, with a plateau at the RP2D, and there was no apparent exposure-response trend for safety or other efficacy endpoints. These analyses support the RP2D of teclistamab in patients with RRMM.
CLINICAL TRIAL REGISTRATION
NCT03145181 (phase I, 09 May 2017); NCT04557098 (phase II, 21 September 2020).
Topics: Humans; Multiple Myeloma; Antineoplastic Agents; Proteasome Inhibitors; Neutropenia; Body Weight
PubMed: 37713090
DOI: 10.1007/s11523-023-00989-z -
PloS One 2022Acute lymphoblastic leukemia (ALL) is a disease of lymphoid progenitor cells with an often aggressive course and is commonly caused by the BCR-ABL fusion gene t(9;22) in...
Acute lymphoblastic leukemia (ALL) is a disease of lymphoid progenitor cells with an often aggressive course and is commonly caused by the BCR-ABL fusion gene t(9;22) in adults. This fusion gene encodes a constitutively active tyrosine kinase that can be effectively inhibited by tyrosine kinase inhibitors (TKIs), with imatinib being the paradigmatic agent of this class. However, BCR-ABL+ ALL cells rapidly develop mutations against many of the available TKIs, and consecutive disease relapse still results in an overall unfavorable prognosis for patients with this disease. To date, allogeneic stem cell transplantation is the only known curative therapeutic option for the mostly elderly patients with BCR-ABL+ ALL. The discrepancy between the limited therapeutic armamentarium and the growing therapeutic need in an aging population is therefore a reason to test drug combinations against BCR-ABL+ ALL. In this study, we demonstrate that the combination of TKIs with proteasome inhibitors efficiently and under certain conditions synergistically exerts cytotoxic effects in BCR-ABL+ ALL cells in vitro with respect to the induction of apoptosis. Both sole and combined treatment of BCR-ABL+ ALL with the proteasome inhibitors bortezomib and ixazomib, respectively, and TKI causes a significantly greater reduction in cell viability than TKI treatment alone in both BCR-ABL+ cell lines TOM-1 and BV-173. In BV-173 cells, we observed a significant reduction in cell viability to only 1.26%±0.46% with bortezomib treatment and 1.57±0.7% with combination treatment, whereas cells treated with dasatinib alone still had a viable percentage of 40.58±2.6%. Similar results were obtained when ixazomib was applied to both cell lines, and apoptosis was induced in both cases (93.36%±2.7% apoptotic BV-173 cells when treated with ixazomib and TKI). The combination of TKI and proteasome inhibitor is efficient in vitro, potentially expanding the spectrum of therapeutic options for patients with BCR-ABL+ ALL.
Topics: Adult; Aged; Boron Compounds; Bortezomib; Dasatinib; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Glycine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Kinase Inhibitors
PubMed: 36194587
DOI: 10.1371/journal.pone.0268352 -
Frontiers in Immunology 2023The outcome of pancreatic ductal adenocarcinoma (PDAC) remains poor due to few therapeutic options available and challenges with precision therapy to target each...
The outcome of pancreatic ductal adenocarcinoma (PDAC) remains poor due to few therapeutic options available and challenges with precision therapy to target each tumour's specific characteristics. In this study, a biologically meaningful patient stratification-prognostic model with therapeutic suggestion value based on tumor senescence was developed and validated in multiple independent cohorts. Further mechanistic investigation based on single-cell transcriptomic data and experiments revealed that complement derived from non-senescent tumor cells stimulates M1 differentiation and antigen presentation, while senescent tumor cells secrete CCL20 to favor immunosuppressive M2 polarization. Also, senescent phenotype depends on proteasome function, suggesting that high-risk, high-senescence patients may benefit from proteasome inhibitors, which reverse senescence-mediated resistance to conventional chemotherapy and improve outcome. In conclusion, the current study identified senescence as a tumor-specific, hazardous factor associated with immunosuppression in PDAC. Mechanistically, senescence abrogates complement-induced M1 activation and antigen presentation, and upregulates CCL20 to favor M2 polarization. The senescence-related risk model is prognostic and therapeutic-suggestive. In light of the reliance of senescent cells on proteasomal functions, proteasome inhibitors are promising agents for high-risk patients with senescent PDAC.
Topics: Humans; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Immunosuppression Therapy; Chemokine CCL20
PubMed: 37398643
DOI: 10.3389/fimmu.2023.1216376 -
Cells Aug 2023Protein turnover, a highly regulated process governed by the ubiquitin-proteasome system (UPS), is essential for maintaining cellular homeostasis. Dysregulation of the... (Review)
Review
Protein turnover, a highly regulated process governed by the ubiquitin-proteasome system (UPS), is essential for maintaining cellular homeostasis. Dysregulation of the UPS has been implicated in various diseases, including viral infections and cancer, making the proteins in the UPS attractive targets for therapeutic intervention. However, the functional and structural redundancies of UPS enzymes present challenges in identifying precise drug targets and achieving target selectivity. Consequently, only 26S proteasome inhibitors have successfully advanced to clinical use thus far. To overcome these obstacles, engineered peptides and proteins, particularly engineered ubiquitin, have emerged as promising alternatives. In this review, we examine the impact of engineered ubiquitin on UPS and non-UPS proteins, as well as on viral enzymes. Furthermore, we explore their potential to guide the development of small molecules targeting novel surfaces, thereby expanding the range of druggable targets.
Topics: Proteasome Endopeptidase Complex; Ubiquitin; Cytoplasm; Proteolysis; Proteasome Inhibitors
PubMed: 37626927
DOI: 10.3390/cells12162117 -
Hematology. American Society of... Dec 2020The management of Waldenström macroglobulinemia (WM) has evolved tremendously with recent genomic discoveries that correlate with clinical presentation and could help... (Review)
Review
The management of Waldenström macroglobulinemia (WM) has evolved tremendously with recent genomic discoveries that correlate with clinical presentation and could help to tailor treatment approaches. The current diagnosis of WM requires clinicopathological criteria, including bone marrow involvement by lymphoplasmacytic lymphoma cells, a serum immunoglobulin M (IgM) monoclonal paraprotein, and presence of the MYD88 L265P mutation. Once the diagnosis is established, the relationship between the patient's symptoms and WM should be carefully investigated, because therapy should be reserved for symptomatic patients. Bone marrow involvement and serum levels of IgM, albumin, and β2-microglobulin can be used to estimate the time until treatment initiation. The treatment of WM patients should be highly personalized, and the patient's clinical presentation, comorbidities, genomic profile, and preferences, as well as toxicity of the treatment regimens, should be taken into account. Alkylating agents (bendamustine, cyclophosphamide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), anti-CD20 monoclonal antibodies (rituximab, ofatumumab), and Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) are safe and highly effective treatment options in patients with WM. Because novel covalent and noncovalent BTK inhibitors (tirabrutinib, vecabrutinib, LOXO-305, ARQ-531), BCL2 antagonists (venetoclax), and CXCR4-targeting agents (ulocuplumab, mavorixafor) are undergoing clinical development in WM, the future of WM therapy certainly appears bright and hopeful.
Topics: Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Immunological; Disease Management; Genomics; Humans; Male; Molecular Targeted Therapy; Proteasome Inhibitors; Protein Kinase Inhibitors; Waldenstrom Macroglobulinemia
PubMed: 33275726
DOI: 10.1182/hematology.2020000121 -
Cell Chemical Biology May 2023In this issue of Cell Chemical Biology, Zhan et al. report dual-pharmacophore molecules ("artezomibs"), combining an artemisinin and proteasome inhibitor that exhibit...
In this issue of Cell Chemical Biology, Zhan et al. report dual-pharmacophore molecules ("artezomibs"), combining an artemisinin and proteasome inhibitor that exhibit potent activity against both wild-type and drug-resistant malarial parasites. This study indicates that artezomibs offer a promising approach to combat drug resistance encountered by current antimalarial therapies.
Topics: Antimalarials; Proteasome Endopeptidase Complex; Drug Resistance; Proteasome Inhibitors
PubMed: 37207629
DOI: 10.1016/j.chembiol.2023.04.012 -
Fluids and Barriers of the CNS Oct 2023Loss of P-glycoprotein (P-gp) at the blood-brain barrier contributes to amyloid-β (Aβ) brain accumulation in Alzheimer's disease (AD). Using transgenic human amyloid...
BACKGROUND
Loss of P-glycoprotein (P-gp) at the blood-brain barrier contributes to amyloid-β (Aβ) brain accumulation in Alzheimer's disease (AD). Using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576), we previously showed that Aβ triggers P-gp loss by activating the ubiquitin-proteasome pathway, which leads to P-gp degradation. Furthermore, we showed that inhibiting the ubiquitin-activating enzyme (E1) prevents P-gp loss and lowers Aβ accumulation in the brain of hAPP mice. Based on these data, we hypothesized that repurposing the FDA-approved proteasome inhibitor, bortezomib (Velcade; BTZ), protects blood-brain barrier P-gp from degradation in hAPP mice in vivo.
METHODS
We treated hAPP mice with the proteasome inhibitor BTZ or a combination of BTZ with the P-gp inhibitor cyclosporin A (CSA) for 2 weeks. Vehicle-treated wild-type (WT) mice were used as a reference for normal P-gp protein expression and transport activity. In addition, we used the opioid receptor agonist loperamide as a P-gp substrate in tail flick assays to indirectly assess P-gp transport activity at the blood-brain barrier in vivo. We also determined P-gp protein expression by Western blotting, measured P-gp transport activity levels in isolated brain capillaries with live cell confocal imaging and assessed Aβ plasma and brain levels with ELISA.
RESULTS
We found that 2-week BTZ treatment of hAPP mice restored P-gp protein expression and transport activity in brain capillaries to levels found in WT mice. We also observed that hAPP mice displayed significant loperamide-induced central antinociception compared to WT mice indicating impaired P-gp transport activity at the blood-brain barrier of hAPP mice in vivo. Furthermore, BTZ treatment prevented loperamide-induced antinociception suggesting BTZ protected P-gp loss in hAPP mice. Further, BTZ-treated hAPP mice had lower Aβ40 and Aβ42 brain levels compared to vehicle-treated hAPP mice.
CONCLUSIONS
Our data indicate that BTZ protects P-gp from proteasomal degradation in hAPP mice, which helps to reduce Aβ brain levels. Our data suggest that the proteasome system could be exploited for a novel therapeutic strategy in AD, particularly since increasing Aβ transport across the blood-brain barrier may prove an effective treatment for patients.
Topics: Humans; Mice; Animals; Alzheimer Disease; Blood-Brain Barrier; Proteasome Endopeptidase Complex; Loperamide; Proteasome Inhibitors; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Brain; Mice, Transgenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily B
PubMed: 37803468
DOI: 10.1186/s12987-023-00470-z