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Journal of Hematology & Oncology Nov 2020The outcomes of multiple myeloma (MM) have been improved significantly with the therapies incorporating proteasome inhibitors (PI), immunomodulatory drugs, monoclonal... (Review)
Review
The outcomes of multiple myeloma (MM) have been improved significantly with the therapies incorporating proteasome inhibitors (PI), immunomodulatory drugs, monoclonal antibodies (MoAb) and stem cell transplantation. However, relapsed and refractory MM (RRMM) remains a major challenge. Novel agents and regimens are under active clinical development. These include new PIs such as ixazomib, marizomib, and oprozomib; new MoAbs such as isatuximab and MOR202; novel epigenetic agent ricolinostat and novel cytokines such as siltuximab. Recently, the first XPO-1 inhibitor, selinexor, was approved for RRMM. BCMA-targeted BiTE, antibody-drug conjugates and CAR-T cells have the potential to revolutionize the therapy for RRMM. In this review, we summarized the latest clinical development of these novel agents and regimens.
Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Immune Checkpoint Inhibitors; Immunoconjugates; Immunotherapy, Adoptive; Multiple Myeloma; Proteasome Inhibitors
PubMed: 33168044
DOI: 10.1186/s13045-020-00980-5 -
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 -
The Journal of Antibiotics Apr 2019Lactacystin exemplifies the role that serendipity plays in drug discovery and why "finding things without actually looking for them" retains such a pivotal role in the... (Review)
Review
Lactacystin exemplifies the role that serendipity plays in drug discovery and why "finding things without actually looking for them" retains such a pivotal role in the search for the useful properties of chemicals. The first proteasome inhibitor discovered, lactacystin stimulated new possibilities in cancer control. New and innovative uses are regularly being found for lactacystin, including as a model to study dementia, while new formulations and delivery systems may facilitate its use clinically as an anticancer agent. All this provides yet more evidence that we need a comprehensive, collaborative and coordinated programme to fully investigate all new and existing chemical compounds, especially those of microbial origin. We need to do so in order to avoid failing to detect and successfully exploit unsought yet potentially life-saving or extremely advantageous properties of microbial metabolites.
Topics: Acetylcysteine; Antibiotics, Antineoplastic; Biological Products; Dementia; Drug Discovery; Humans; Neoplasms; Neuroprotective Agents; Proteasome Inhibitors
PubMed: 30755736
DOI: 10.1038/s41429-019-0141-8 -
Frontiers in Immunology 2022Multiple myeloma is an incurable cancer of plasma cells that is predominantly located in the bone marrow. Multiple myeloma cells are characterized by distinctive... (Review)
Review
Multiple myeloma is an incurable cancer of plasma cells that is predominantly located in the bone marrow. Multiple myeloma cells are characterized by distinctive biological features that are intricately linked to their core function, the assembly and secretion of large amounts of antibodies, and their diverse interactions with the bone marrow microenvironment. Here, we provide a concise and introductory discussion of major metabolic hallmarks of plasma cells and myeloma cells, their roles in myeloma development and progression, and how they could be exploited for therapeutic purposes. We review the role of glucose consumption and catabolism, assess the dependency on glutamine to support key metabolic processes, and consider metabolic adaptations in drug-resistant myeloma cells. Finally, we examine the complex metabolic effects of proteasome inhibitors on myeloma cells and the extracellular matrix, and we explore the complex relationship between myeloma cells and bone marrow adipocytes.
Topics: Bone Marrow; Humans; Multiple Myeloma; Proteasome Inhibitors; Tumor Microenvironment
PubMed: 36072593
DOI: 10.3389/fimmu.2022.897862 -
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 -
EBioMedicine Apr 2022Multiple myeloma (MM) is still an incurable malignancy of plasma cells. Proteasome inhibitors (PIs) work as the backbone agent and have greatly improved the outcome in...
BACKGROUND
Multiple myeloma (MM) is still an incurable malignancy of plasma cells. Proteasome inhibitors (PIs) work as the backbone agent and have greatly improved the outcome in majority of newly diagnosed patients with myeloma. However, drug resistance remains the major obstacle causing treatment failure in clinical practice. Here, we investigated the effects of Indirubin-3'-monoxime (I3MO), one of the derivatives of Indirubin, in the treatment of MM.
METHODS
MM patient primary samples and human cell lines were examined. I3MO effects on myeloma treatment and the underling molecular mechanisms were investigated via in vivo and in vitro study.
FINDINGS
Our results demonstrated the anti-MM activity of I3MO in both drug- sensitive and -resistance MM cells. I3MO sensitizes MM cells to bortezomib-induced apoptosis. Mechanistically, I3MO acts as a multifaceted regulator of cell death, which induced DNA damage, cell cycle arrest, and abrogates NF-κB activation. I3MO efficiently down-regulated USP7 expression, promoted NEK2 degradation, and suppressed NF-κB signaling in MM. Our study reported that I3MO directly bound with and caused the down-regulation of PA28γ (PSME3), and PA200 (PSME4), the proteasome activators. Knockdown of PSME3 or PSME4 caused the inhibition of proteasome capacity and the overload of paraprotein, which sensitizes MM cells to bortezomib-mediated growth arrest. Clinical data demonstrated that PSME3 and PSME4 are over-expressed in relapsed/refractory MM (RRMM) and associated with inferior outcome.
INTERPRETATION
Altogether, our study indicates that I3MO is agent triggering proteasome inhibition and represents a promising therapeutic strategy to improve patient outcome in MM.
FUNDINGS
A full list of funding can be found in the acknowledgements.
Topics: Antineoplastic Agents; Apoptosis; Bortezomib; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Indoles; Multiple Myeloma; NF-kappa B; NIMA-Related Kinases; Oximes; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Ubiquitin-Specific Peptidase 7
PubMed: 35344764
DOI: 10.1016/j.ebiom.2022.103950 -
Bone May 2016Bone disease is a characteristic feature of multiple myeloma, a malignant plasma cell dyscrasia. In patients with multiple myeloma, the normal process of bone remodeling... (Review)
Review
Bone disease is a characteristic feature of multiple myeloma, a malignant plasma cell dyscrasia. In patients with multiple myeloma, the normal process of bone remodeling is dysregulated by aberrant bone marrow plasma cells, resulting in increased bone resorption, prevention of new bone formation, and consequent bone destruction. The ubiquitin-proteasome system, which is hyperactive in patients with multiple myeloma, controls the catabolism of several proteins that regulate bone remodeling. Clinical studies have reported that treatment with the first-in-class proteasome inhibitor bortezomib reduces bone resorption and increases bone formation and bone mineral density in patients with multiple myeloma. Since the introduction of bortezomib in 2003, several next-generation proteasome inhibitors have also been used clinically, including carfilzomib, oprozomib, ixazomib, and delanzomib. This review summarizes the available preclinical and clinical evidence regarding the effect of proteasome inhibitors on bone remodeling in multiple myeloma.
Topics: Animals; Bone Remodeling; Humans; Models, Biological; Multiple Myeloma; Proteasome Inhibitors
PubMed: 26947893
DOI: 10.1016/j.bone.2016.02.019 -
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 -
Cancer Treatment Reviews Dec 2015Although survival outcomes have improved over the last decade for patients with multiple myeloma (MM), few patients remain free of disease and most inevitably relapse.... (Review)
Review
Although survival outcomes have improved over the last decade for patients with multiple myeloma (MM), few patients remain free of disease and most inevitably relapse. Selecting a treatment for patients with relapsed MM is challenging given the number and diversity of regimens patients may have previously received, which can affect subsequent therapeutic choices. Importantly, a number of patient- and disease-related factors can also have an effect on treatment choice, treatment efficacy, and tolerability; thus, an understanding of the heterogeneity of patients in the setting of relapsed MM is important for appropriate treatment selection. Here, we review select patient and disease characteristics reported in key interventional and observational studies in relapsed MM (including age, sex, race, and the presence of high-risk disease, renal impairment, or peripheral neuropathy at baseline) to examine common and disparate features of patients with relapsed MM. As therapeutic regimens can have varying efficacy and/or tolerability in patients depending on these factors, we also provide treatment recommendations for patients with select baseline characteristics.
Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Immunologic Factors; Multiple Myeloma; Neoplasm Recurrence, Local; Paraneoplastic Polyneuropathy; Proteasome Inhibitors; Sex Factors
PubMed: 26296679
DOI: 10.1016/j.ctrv.2015.07.005 -
Endocrine-related Cancer Feb 2015The destruction of proteins via the ubiquitin-proteasome system is a multi-step, complex process involving polyubiquitination of substrate proteins, followed by... (Review)
Review
The destruction of proteins via the ubiquitin-proteasome system is a multi-step, complex process involving polyubiquitination of substrate proteins, followed by proteolytic degradation by the macromolecular 26S proteasome complex. Inhibitors of the proteasome promote the accumulation of proteins that are deleterious to cell survival, and represent promising anti-cancer agents. In multiple myeloma and mantle cell lymphoma, treatment with the first-generation proteasome inhibitor, bortezomib, or the second-generation inhibitor, carfilzomib, has demonstrated significant therapeutic benefit in humans. This has prompted United States Food and Drug Administration (US FDA) approval of these agents and development of additional second-generation compounds with improved properties. There is considerable interest in extending the benefits of proteasome inhibitors to the treatment of solid tumor malignancies. Herein, we review progress that has been made in the preclinical development and clinical evaluation of different proteasome inhibitors in solid tumors. In addition, we describe several novel approaches that are currently being pursued for the treatment of solid tumors, including drug combinatorial strategies incorporating proteasome inhibitors and the targeting of components of the ubiquitin-proteasome system that are distinct from the 26S proteasome complex.
Topics: Animals; Combined Modality Therapy; Humans; Molecular Targeted Therapy; Neoplasms; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Ubiquitin
PubMed: 24659480
DOI: 10.1530/ERC-14-0005