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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 -
Journal of Hematology & Oncology Jan 2023Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance... (Review)
Review
Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies.
Topics: Humans; Proteolysis; Bortezomib; Ubiquitin-Protein Ligases; Proteasome Endopeptidase Complex; Ubiquitination; Molecular Chaperones; Drug Resistance; Neoplasms
PubMed: 36694209
DOI: 10.1186/s13045-023-01398-5 -
Disease Models & Mechanisms Dec 2022The proteosome inhibitor bortezomib has revolutionized the treatment of multiple hematologic malignancies, but in many cases, its efficacy is limited by a dose-dependent...
The proteosome inhibitor bortezomib has revolutionized the treatment of multiple hematologic malignancies, but in many cases, its efficacy is limited by a dose-dependent peripheral neuropathy. We show that human induced pluripotent stem cell (hiPSC)-derived motor neurons and sensory neurons provide a model system for the study of bortezomib-induced peripheral neuropathy, with promising implications for furthering the mechanistic understanding of and developing treatments for preventing axonal damage. Human neurons in tissue culture displayed distal-to-proximal neurite degeneration when exposed to bortezomib. This process coincided with disruptions in mitochondrial function and energy homeostasis, similar to those described in rodent models of bortezomib-induced neuropathy. Moreover, although the degenerative process was unaffected by inhibition of caspases, it was completely blocked by exogenous nicotinamide adenine dinucleotide (NAD+), a mediator of the SARM1-dependent axon degeneration pathway. We demonstrate that bortezomib-induced neurotoxicity in relevant human neurons proceeds through mitochondrial dysfunction and NAD+ depletion-mediated axon degeneration, raising the possibility that targeting these changes might provide effective therapeutics for the prevention of bortezomib-induced neuropathy and that modeling chemotherapy-induced neuropathy in human neurons has utility.
Topics: Humans; NAD; Bortezomib; Induced Pluripotent Stem Cells; Peripheral Nervous System Diseases
PubMed: 36398590
DOI: 10.1242/dmm.049358 -
Bioscience Reports Aug 2017Multiple myeloma (MM) is a B-cell neoplasm with a high incidence of relapse. Bortezomib has been extensively studied for the maintenance treatment of MM. Here, we... (Meta-Analysis)
Meta-Analysis Review
Multiple myeloma (MM) is a B-cell neoplasm with a high incidence of relapse. Bortezomib has been extensively studied for the maintenance treatment of MM. Here, we carried out a meta-analysis to determine the efficacy and safety of maintenance therapy with bortezomib. We searched for clinical trials in PubMed (Medline), Embase (OVID), and the Cochrane Library. Two randomized controlled trials (RCTs) enrolling a total of 1338 patients were included. Bortezomib maintenance statistically significantly improved both progression-free survival (PFS) (hazard ratio (HR) 0.67, 95% confidence interval (CI) = 0.51 to 0.87, =0.003) and overall survival (OS) (HR = 0.75 therapy, 95% CI = 0.63 to 0.89, =0.001) more than did non-bortezomib maintenance therapy. Our analysis revealed higher incidence of neutropenia (risks ratios (RR) = 1.39; 95% CI = 1.08 to 1.79), peripheral neuropathy (PN) (RR = 2.23; 95% CI = 1.38 to 3.61, =0.001), and cardiologic events (RR = 1.91; 95% CI = 1.12 to 3.28, =0.02) in patients with bortezomib maintenance therapy. Our meta-analysis demonstrates OS and PFS benefits of bortezomib maintenance therapy in patients with newly diagnosed MM. However, the therapy is associated with increased risk of adverse events. Additionally, more RCTs are needed for better understanding and determination of optimal bortezomib maintenance therapy in MM.
Topics: Bortezomib; Disease-Free Survival; Female; Humans; Male; Multiple Myeloma; Survival Rate
PubMed: 28706008
DOI: 10.1042/BSR20170304 -
Critical Reviews in Oncology/hematology May 2024Bortezomib is the first-line standard and most effective chemotherapeutic for multiple myeloma; however, bortezomib-induced peripheral neuropathy (BIPN) severely affects... (Review)
Review
Bortezomib is the first-line standard and most effective chemotherapeutic for multiple myeloma; however, bortezomib-induced peripheral neuropathy (BIPN) severely affects the chemotherapy regimen and has long-term impact on patients under maintenance therapy. The pathogenesis of BIPN is poorly understood, and basic research and development of BIPN management drugs are in early stages. Besides chemotherapy dose reduction and regimen modification, no recommended prevention and treatment approaches are available for BIPN apart from the International Myeloma Working Group guidelines for peripheral neuropathy in myeloma. An in-depth exploration of the pathogenesis of BIPN, development of additional therapeutic approaches, and identification of risk factors are needed. Optimizing effective and standardized BIPN treatment plans and providing more decision-making evidence for clinical diagnosis and treatment of BIPN are necessary. This article reviews the recent advances in BIPN research; provides an overview of clinical features, underlying molecular mechanisms, and therapeutic approaches; and highlights areas for future studies.
Topics: Humans; Bortezomib; Peripheral Nervous System Diseases; Antineoplastic Agents; Multiple Myeloma
PubMed: 38615869
DOI: 10.1016/j.critrevonc.2024.104353 -
Blood Aug 2022Triplet regimens, such as lenalidomide, bortezomib, and dexamethasone (RVd) or thalidomide, bortezomib, and dexamethasone (VTd), are standard induction therapies for...
Triplet regimens, such as lenalidomide, bortezomib, and dexamethasone (RVd) or thalidomide, bortezomib, and dexamethasone (VTd), are standard induction therapies for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to RVd and VTd has been investigated in the GRIFFIN and CASSIOPEIA trials, respectively, resulting in improvement in the rate of minimal residual disease (MRD) negativity. In this study, we conducted a cost-effectiveness analysis with a 10-year time horizon to compare first-line and second-line use of daratumumab for transplant-eligible patients with NDMM. Because long-term follow-up data for these clinical trials are not yet available, we developed a Markov model that uses MRD status to predict progression-free survival. Daratumumab was used either in the first-line setting in combination with RVd or VTd or in the second-line setting with carfilzomib plus dexamethasone (Kd). Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios were calculated from a Japanese and US payer perspective. In the Japanese analysis, D-RVd showed higher QALYs (5.43 vs 5.18) and lower costs (¥64 479,793 vs ¥71 287 569) compared with RVd, and D-VTd showed higher QALYs (5.67 vs 5.42) and lower costs (¥43 600 310 vs ¥49 471,941) compared with VTd. Similarly, the US analysis demonstrated dominance of a strategy incorporating daratumumab in first-line treatment regimens. Given that overall costs are reduced and outcomes are improved when daratumumab is used as part of a first-line regimen, the economic analysis indicates that addition of daratumumab to first-line RVd and VTd regimens is a dominant strategy compared with reserving its use for the second-line setting.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cost-Benefit Analysis; Dexamethasone; Humans; Multiple Myeloma; Thalidomide
PubMed: 35580269
DOI: 10.1182/blood.2021015220 -
PloS One 2022The combination of panobinostat, bortezomib and dexamethasone (PanBorDex) is available as a treatment option for relapsed refractory multiple myeloma (RRMM) based on the...
The combination of panobinostat, bortezomib and dexamethasone (PanBorDex) is available as a treatment option for relapsed refractory multiple myeloma (RRMM) based on the PANORAMA-1 trial which investigated this triplet in early relapse. In routine clinical care, PanBorDex is used primarily in later relapses and is commonly administered in attenuated dosing schedules to mitigate the treatment-related toxicity. We set out to evaluate efficacy and safety outcomes with PanBorDex later in the disease course and evaluate the role of attenuated dosing schedules. This was a retrospective evaluation of patients treated in routine clinical practice between 2016-2019 across seven heamatology centres in the UK; patients who received at least one dose of PanBorDex were eligible for inclusion. The dosing schedule of panobinostat (10mg, 15mg or 20mg, twice or three times a week) and bortezomib (0.7mg/m2, 1mg/m2 or 1.3mg/m2 once or twice weekly) was as per treating physician choice. Patients received treatment until disease progression or unacceptable toxicity. The primary outcome is response rates according to IMWG criteria. Key secondary endpoints include progression-free survival (PFS) and overall survival (OS). Other secondary endpoints include rates of adverse events according to CTCAE criteria. In total, 61 patients were eligible for inclusion and received PanBorDex primarily as ≥5th line of treatment. One third of patients received PanBorDex at full dose, for the remaining two thirds, treatment was given in reduced dose intensities. The overall response rate was 44.2%, including 14.7% very good partial response (VGPR) rates; 68.8% of patients derived clinical benefit with stable disease or better. The median PFS was 3.4 months; non-refractory patients and those who achieved VGPR benefited from prolonged PFS of 11.4 months and 17.7 months, respectively. The median OS was 9.5 months. The triplet was associated with 45% and 18% incidence of grade 3-4 thrombocytopenia and diarrhea, respectively.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Humans; Multiple Myeloma; Panobinostat; Retrospective Studies; United Kingdom
PubMed: 35797277
DOI: 10.1371/journal.pone.0270854 -
Experimental & Molecular Medicine Nov 2022Both the tumor and tumor microenvironment (TME) are crucial for pathogenesis and chemotherapy resistance in multiple myeloma (MM). Bortezomib, commonly used for MM...
Both the tumor and tumor microenvironment (TME) are crucial for pathogenesis and chemotherapy resistance in multiple myeloma (MM). Bortezomib, commonly used for MM treatment, works on both MM and TME cells, but innate and acquired resistance easily develop. By single-cell RNA sequencing (scRNA-seq), we investigated bone marrow aspirates of 18 treatment-naïve MM patients who later received bortezomib-based treatments. Twelve plasma and TME cell types and their subsets were identified. Suboptimal responders (SORs) to bortezomib exhibited higher copy number alteration burdens than optimal responders (ORs). Forty-four differentially expressed genes for SORs based on scRNA-seq data were further analyzed in an independent cohort of 90 treatment-naïve MMs, where 24 genes were validated. A combined model of three clinical variables (older age, low absolute lymphocyte count, and no autologous stem cell transplantation) and 24 genes was associated with bortezomib responsiveness and poor prognosis. In T cells, cytotoxic memory, proliferating, and dysfunctional subsets were significantly enriched in SORs. Moreover, we identified three monocyte subsets associated with bortezomib responsiveness and an MM-specific NK cell trajectory that ended with an MM-specific subset. scRNA-seq predicted the interaction of the GAS6-MERTK, ALCAM-CD6, and BAG6-NCR gene networks. Of note, tumor cells from ORs and SORs were the most prominent sources of ALCAM on effector T cells and BAG6 on NK cells, respectively. Our results indicate that the complicated compositional and molecular changes of both tumor and immune cells in the bone marrow (BM) milieu are important in the development and acquisition of resistance to bortezomib-based treatment of MM.
Topics: Humans; Activated-Leukocyte Cell Adhesion Molecule; Bortezomib; Molecular Chaperones; Multiple Myeloma; Single-Cell Analysis; Tumor Microenvironment
PubMed: 36380017
DOI: 10.1038/s12276-022-00884-z -
Communications Biology Dec 2023TRPV1 is an ion channel that transduces noxious heat and chemical stimuli and is expressed in small fiber primary sensory neurons that represent almost half of skin...
TRPV1 is an ion channel that transduces noxious heat and chemical stimuli and is expressed in small fiber primary sensory neurons that represent almost half of skin nerve terminals. Tissue injury and inflammation result in the sensitization of TRPV1 and sustained activation of TRPV1 can lead to cellular toxicity though calcium influx. To identify signals that trigger TRPV1 sensitization after a 24-h exposure, we developed a phenotypic assay in mouse primary sensory neurons and performed an unbiased screen with a compound library of 480 diverse bioactive compounds. Chemotherapeutic agents, calcium ion deregulators and protein synthesis inhibitors were long-acting TRPV1 sensitizers. Amongst the strongest TRPV1 sensitizers were proteasome inhibitors, a class that includes bortezomib, a chemotherapeutic agent that causes small fiber neuropathy in 30-50% of patients. Prolonged exposure of bortezomib produced a TRPV1 sensitization that lasted several days and neurite retraction in vitro and histological and behavioral changes in male mice in vivo. TRPV1 knockout mice were protected from epidermal nerve fiber loss and a loss of sensory discrimination after bortezomib treatment. We conclude that long-term TRPV1 sensitization contributes to the development of bortezomib-induced neuropathy and the consequent loss of sensation, major deficits experienced by patients under this chemotherapeutic agent.
Topics: Humans; Mice; Male; Animals; Bortezomib; TRPV Cation Channels; Calcium; Skin; Mice, Knockout
PubMed: 38052846
DOI: 10.1038/s42003-023-05624-1 -
Advanced Healthcare Materials Apr 2022Multiple myeloma (MM) is a malignancy of plasma cells accounting for ≈12% of hematological malignancies. In this study, the fabrication of a high-content in vitro MM...
Multiple myeloma (MM) is a malignancy of plasma cells accounting for ≈12% of hematological malignancies. In this study, the fabrication of a high-content in vitro MM model using a coaxial extrusion bioprinting method is reported, allowing formation of a human bone marrow-like microenvironment featuring an outer mineral-containing sheath and the inner soft hydrogel-based core. MM cells are mono-cultured or co-cultured with HS5 stromal cells that can release interleukin-6 (IL-6), where the cells show superior behaviors and responses to bortezomib in 3D models than in the planar cultures. Tocilizumab, a recombinant humanized anti-IL-6 receptor (IL-6R), is investigated for its efficacy to enhance the chemosensitivity of bortezomib on MM cells cultured in the 3D model by inhibiting IL-6R. More excitingly, in a proof-of-concept demonstration, it is revealed that patient-derived MM cells can be maintained in 3D-bioprinted microenvironment with decent viability for up to 7 days evaluated, whereas they completely die off in planar culture as soon as 5 days. In conclusion, a 3D-bioprinted MM model is fabricated to emulate some characteristics of the human bone marrow to promote growth and proliferation of the encapsulated MM cells, providing new insights for MM modeling, drug development, and personalized therapy in the future.
Topics: Bioprinting; Bortezomib; Coculture Techniques; Humans; Hydrogels; Multiple Myeloma; Printing, Three-Dimensional; Tissue Engineering; Tumor Microenvironment
PubMed: 34558232
DOI: 10.1002/adhm.202100884