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Pharmacology & Therapeutics Sep 2020Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its...
Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.
Topics: Cyclin-Dependent Kinases; Drug Resistance; E2F4 Transcription Factor; Holoenzymes; Humans; Lipid Droplets; Molecular Chaperones; Muscle Proteins; NF-kappa B; Neoplasms; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteostasis; Tumor Suppressor Protein p53; Ubiquitin
PubMed: 32442437
DOI: 10.1016/j.pharmthera.2020.107579 -
Hematology (Amsterdam, Netherlands) Dec 2022Despite conspicuous advances in innovating novel drugs and combination regimens in multiple myeloma (MM) in recent decades, the most appropriate maintenance regimens... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Despite conspicuous advances in innovating novel drugs and combination regimens in multiple myeloma (MM) in recent decades, the most appropriate maintenance regimens after inductive therapy are still controversial and opaque.
OBJECTIVE
We aimed to identify the most effective maintenance treatment for newly diagnosed multiple myeloma (NDMM) patients via network meta-analysis.
METHOD
We searched PubMed, Embase, Cochrane Library, Scopus, and Google Scholars from inception to April, 2022. Odds ratios (ORs) were generated for dichotomous variants. The primary endpoint was overall survival (OS).
RESULTS
Eventually a total of 19 trials, including 11 treatments and 8337 patients, were included in this analysis. For OS, lenalidomide (OR ranged from 1.61 to 1.99) and daratumumab (OR ranged from 1.83 to 2.41) showed significant efficacy over placebo. Maintenance therapy comprising lenalidomide-carfilzomib (OR ranged from 3.19 to 6.95), lenalidomide-prednisone (OR ranged from 2.62 to 4.44), bortezomib-thalidomide (OR ranged from 2.48 to 3.64), daratumumab (OR ranged from 2.0 to 2.98), lenalidomide (OR ranged from 1.4 to 3.19), ixazomib (OR ranged from 1.36 to 2.05), thalidomide (OR ranged from 1.5 to 1.86) demonstrated significant effects in prolongin PFS compared with placebo; Among the efficient therapies, lenalidomide-carfilzomib was significantly superior to lenalidomide (OR ranged from 2.18 to 2.20), daratumumab (OR ranged from 1.49 to 2.66) and ixazomib (OR ranged from 2.75 to 3.57).
CONCLUSION
Considering OS and PFS, lenalidomide-carfilzomib should be recommended as the best therapy. In clinical practice, this must be weighed against the increased risk of adverse events and financial burden. However, more head-to-head studies are needed to confirm these findings.
Topics: Antineoplastic Combined Chemotherapy Protocols; Boron Compounds; Bortezomib; Glycine; Humans; Lenalidomide; Multiple Myeloma; Network Meta-Analysis; Prednisone; Thalidomide
PubMed: 36125238
DOI: 10.1080/16078454.2022.2121900 -
Future Medicinal Chemistry Oct 2019Proteolysis-targeting chimeras (PROTACs) have received much attention for their promising therapeutic intervention in recent years. These molecules, with the mechanism...
Proteolysis-targeting chimeras (PROTACs) have received much attention for their promising therapeutic intervention in recent years. These molecules, with the mechanism of simultaneous recruitment of target protein and an E3 ligase, can trigger the cellular ubiquitin-proteasome system to degrade the target proteins. This article systematically introduces the mechanism of small-molecule PROTACs, and summarized the research progress of small-molecule PROTACs. The prospect for further application and the problems to be solved are also discussed.
Topics: Cell Line, Tumor; Humans; Proteasome Endopeptidase Complex; Proteolysis; Recombinant Fusion Proteins; Ubiquitin
PubMed: 31571504
DOI: 10.4155/fmc-2019-0161 -
BMC Cancer May 2023Upfront high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) remains a profitable strategy for newly diagnosed multiple myeloma (MM) patients... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Upfront high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) remains a profitable strategy for newly diagnosed multiple myeloma (MM) patients in the context of novel agents. However, current knowledge demonstrates a discrepancy between progression-free survival (PFS) and overall survival (OS) benefit with HDT/ASCT.
METHODS
We conducted a systematic review and meta-analysis that included both randomized controlled trials (RCTs) and observational studies evaluating the benefit of upfront HDT/ASCT published during 2012 to 2023. Further sensitivity analysis and meta-regression were also performed.
RESULTS
Among the 22 enrolled studies, 7 RCTs and 9 observational studies had a low or moderate risk of bias, while the remaining 6 observational studies had a serious risk of bias. HDT/ASCT revealed advantages in complete response (CR) with an odds ratio (OR) of 1.24 and 95% confidence interval (CI) 1.02 ~ 1.51, PFS with a hazard ratio (HR) of 0.53 (95% CI 0.46 ~ 0.62), and OS with an HR of 0.58 (95% CI 0.50 ~ 0.69). Sensitivity analysis excluding the studies with serious risk of bias and trim-and-fill imputation fundamentally confirmed these findings. Older age, increased percentage of patients with International Staging System (ISS) stage III or high-risk genetic features, decreased proteasome inhibitor (PI) or combined PI/ immunomodulatory drugs (IMiD) utilization, and decreased follow-up duration or percentage of males were significantly related to a greater survival advantage with HDT/ASCT.
CONCLUSIONS
Upfront ASCT remains a beneficial treatment for newly diagnosed MM patients in the period of novel agents. Its advantage is especially acute in high-risk MM populations, such as elderly individuals, males, those with ISS stage III or high-risk genetic features, but is attenuated with PI or combined PI/IMiD utilization, contributing to divergent survival outcomes.
Topics: Male; Humans; Aged; Multiple Myeloma; Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Disease-Free Survival; Stem Cell Transplantation
PubMed: 37193978
DOI: 10.1186/s12885-023-10907-1 -
Journal of Zhejiang University....The aim of this study is to summarize preclinical studies on herbal medicines used to treat cancer cachexia and its underlying mechanisms. (Review)
Review
OBJECTIVE
The aim of this study is to summarize preclinical studies on herbal medicines used to treat cancer cachexia and its underlying mechanisms.
METHODS
We searched four representing databases, including PubMed, EMBASE, the Allied and Complementary Medicine Database, and the Web of Science up to December 2016. Randomized animal studies were included if the effects of any herbal medicine were tested on cancer cachexia. The methodological quality was evaluated by the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADE) checklist.
RESULTS
A total of fourteen herbal medicines and their compounds were identified, including Coptidis Rhizoma, berberine, Bing De Ling, curcumin, Qing-Shu-Yi-Qi-Tang, Scutellaria baicalensis, Hochuekkito, Rikkunshito, hesperidin, atractylodin, Sipjeondaebo-tang, Sosiho-tang, Anemarrhena Rhizoma, and Phellodendri Cortex. All the herbal medicines, except curcumin, have been shown to ameliorate the symptoms of cancer cachexia through anti-inflammation, regulation of the neuroendocrine pathway, and modulation of the ubiquitin proteasome system or protein synthesis.
CONCLUSIONS
This study showed that herbal medicines might be a useful approach for treating cancer cachexia. However, more detailed experimental studies on the molecular mechanisms and active compounds are needed.
Topics: Animals; Cachexia; Herbal Medicine; Medicine, East Asian Traditional; Neoplasms, Experimental; Phytotherapy
PubMed: 30614226
DOI: 10.1631/jzus.B1800171 -
British Journal of Haematology Feb 2024Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological condition. Initial treatment involves plasma exchange (PLEX),...
Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological condition. Initial treatment involves plasma exchange (PLEX), corticosteroids, caplacizumab and rituximab. In relapsed and refractory cases despite initial treatments, further immune-modulating therapy includes the proteasome inhibitor, bortezomib. Evidence for bortezomib in this setting is limited to case reports and case series. We report our experience and perform a systematic review of the literature. We identified 21 publications with 28 unique patients in addition to our cohort of eight patients treated with bortezomib. The median age of patients was 44 years (IQR: 27-53) and 69% female. They were usually in an initial, refractory presentation of iTTP where they had received PLEX, corticosteroids, rituximab and another line of therapy. After bortezomib administration, 72% of patients had a complete response, with 85% maintaining a durable response without relapse at the last follow-up.
Topics: Humans; Female; Adult; Middle Aged; Male; Bortezomib; Rituximab; Purpura, Thrombotic Thrombocytopenic; Retrospective Studies; Purpura, Thrombocytopenic, Idiopathic; Adrenal Cortex Hormones; Plasma Exchange; ADAMTS13 Protein
PubMed: 37571963
DOI: 10.1111/bjh.19035 -
Frontiers in Plant Science 2022The core particle represents the catalytic portions of the 26S proteasomal complex. The genes encoding α- and β-subunits play a crucial role in protecting plants...
The core particle represents the catalytic portions of the 26S proteasomal complex. The genes encoding α- and β-subunits play a crucial role in protecting plants against various environmental stresses by controlling the quality of newly produced proteins. The 20S proteasome gene family has already been reported in model plants such as Arabidopsis and rice; however, they have not been studied in oilseed crops such as rapeseed ( L.). In the present study, we identified 20S proteasome genes for α- (PA) and β-subunits (PB) in through systematically performed gene structure analysis, chromosomal location, conserved motif, phylogenetic relationship, and expression patterns. A total of 82 genes, comprising 35 and 47 of the 20S proteasome, were revealed in the genome. These genes were distributed on all 20 chromosomes of and most of these genes were duplicated on homoeologous chromosomes. The (α1-7) and (β1-7) genes were phylogenetically placed into seven clades. The pattern of expression of all the and genes was also studied using RNA-seq datasets under biotic and abiotic stress conditions. Out of 82 genes, three exhibited high expression under abiotic stresses, whereas two genes were overexpressed in response to biotic stresses at both the seedling and flowering stages. Moreover, an additional eighteen genes were expressed under normal conditions. Overall, the current findings developed our understanding of the organization of the 20S proteasome genes in , and provided specific genes for further functional research in response to abiotic and biotic stresses.
PubMed: 36388569
DOI: 10.3389/fpls.2022.1037206 -
Annals of Hematology Dec 2022With the incorporation of novel agents in earlier lines of therapy, an increasing number of multiple myeloma patients are refractory to traditional classes of drugs.... (Review)
Review
With the incorporation of novel agents in earlier lines of therapy, an increasing number of multiple myeloma patients are refractory to traditional classes of drugs. Selinexor in combination with dexamethasone has emerged as a viable option for heavily pretreated triple-class relapsed and refractory multiple myeloma (RRMM). In this systematic review, we analyzed available literature on the role of selinexor in RRMM. The Boston trial demonstrated that selinexor when combined with dexamethasone and bortezomib is associated with a better depth and duration of response without excessive toxicity, compared with bortezomib and dexamethasone alone. Similarly, selinexor in combination with carfilzomib and dexamethasone was found to have a durable response and tolerable safety profile in both carfilzomib-naive and carfilzomib refractory RRMM patients. Selinexor in combination with IMiDs (lenalidomide and pomalidomide) as well as CD38 monoclonal antibodies (daratumumab) also have promising results. Selinexor combination therapy is both safe and effective for patients with pretreated RRMM.
Topics: Humans; Multiple Myeloma; Bortezomib; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Neoplasm Recurrence, Local
PubMed: 36214853
DOI: 10.1007/s00277-022-04999-1 -
Immunity, Inflammation and Disease May 2023To review the pathogenesis and treatment of multiple myeloma (MM). MM is a hematological malignancy with abnormal plasma cell proliferation in bone marrow. Due to the...
INTRODUCTION
To review the pathogenesis and treatment of multiple myeloma (MM). MM is a hematological malignancy with abnormal plasma cell proliferation in bone marrow. Due to the emergence of drug resistance, MM is still an incurable malignancy, which requires further exploration of pathogenesis and effective therapeutic targets.
METHODS
In this paper, the method of literature review is adopted to obtain the information about MM. Based on the literature, comprehensive and systematic review is made.
RESULTS
MM is a complex pathophysiological process with great heterogeneity, mainly reflected in genomic instability and bone marrow microenvironment. At present, the treatment of MM has made great progress, proteasome inhibitors and immunomodulatory drugs are widely used in clinic. Allogeneic stem cell transplantation may be the only promising cure for MM, and its high transplant-related mortality limits its clinical application.
CONCLUSIONS
The future of MM treatment lies in the development of more targeted therapies, novel immunotherapies, and a better understanding of the disease's molecular and genetic basis.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Immunotherapy; Multiple Myeloma; Tumor Microenvironment
PubMed: 37249283
DOI: 10.1002/iid3.850 -
Frontiers in Oncology 2023Patients with hematological malignancies (HMs), like chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), have a high risk of...
Agents contributing to secondary immunodeficiency development in patients with multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphoma: A systematic literature review.
INTRODUCTION
Patients with hematological malignancies (HMs), like chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), have a high risk of secondary immunodeficiency (SID), SID-related infections, and mortality. Here, we report the results of a systematic literature review on the potential association of various cancer regimens with infection rates, neutropenia, lymphocytopenia, or hypogammaglobulinemia, indicative of SID.
METHODS
A systematic literature search was performed in 03/2022 using PubMed to search for clinical trials that mentioned in the title and/or abstract selected cancer (CLL, MM, or NHL) treatments covering 12 classes of drugs, including B-lineage monoclonal antibodies, CAR T therapies, proteasome inhibitors, kinase inhibitors, immunomodulators, antimetabolites, anti-tumor antibiotics, alkylating agents, Bcl-2 antagonists, histone deacetylase inhibitors, vinca alkaloids, and selective inhibitors of nuclear export. To be included, a publication had to report at least one of the following: percentages of patients with any grade and/or grade ≥3 infections, any grade and/or grade ≥3 neutropenia, or hypogammaglobulinemia. From the relevant publications, the percentages of patients with lymphocytopenia and specific types of infection (fungal, viral, bacterial, respiratory [upper or lower respiratory tract], bronchitis, pneumonia, urinary tract infection, skin, gastrointestinal, and sepsis) were collected.
RESULTS
Of 89 relevant studies, 17, 38, and 34 included patients with CLL, MM, and NHL, respectively. In CLL, MM, and NHL, any grade infections were seen in 51.3%, 35.9% and 31.1% of patients, and any grade neutropenia in 36.3%, 36.4%, and 35.4% of patients, respectively. The highest proportion of patients with grade ≥3 infections across classes of drugs were: 41.0% in patients with MM treated with a B-lineage monoclonal antibody combination; and 29.9% and 38.0% of patients with CLL and NHL treated with a kinase inhibitor combination, respectively. In the limited studies, the mean percentage of patients with lymphocytopenia was 1.9%, 11.9%, and 38.6% in CLL, MM, and NHL, respectively. Two studies reported the proportion of patients with hypogammaglobulinemia: 0-15.3% in CLL and 5.9% in NHL (no studies reported hypogammaglobulinemia in MM).
CONCLUSION
This review highlights cancer treatments contributing to infections and neutropenia, potentially related to SID, and shows underreporting of hypogammaglobulinemia and lymphocytopenia before and during HM therapies.
PubMed: 36824125
DOI: 10.3389/fonc.2023.1098326