scholarly journals Ubiquitin-Proteasome Modulating Dolabellanes and Secosteroids from Soft Coral Clavularia flava

Marine Drugs ◽  
2020 ◽  
Vol 18 (1) ◽  
pp. 39
Author(s):  
Che-Yen Chiu ◽  
Xue-Hua Ling ◽  
Shang-Kwei Wang ◽  
Chang-Yih Duh
Keyword(s):  
Inhibitory Activity ◽  
Structure Elucidation ◽  
Chemical Structure ◽  
Soft Coral ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Structural Elucidation ◽  
Bioactive Molecules ◽  
High Content Screening ◽  
Ubiquitin Proteasome

We performed a high-content screening (HCS) assay aiming to discover bioactive molecules with proteasome inhibitory activity. By structural elucidation, we identified six compounds purified from soft coral Clavularia flava, which potentiates proteasome inhibition. Chemical structure elucidation revealed they are dolabellane- and secosteroid-based compounds including a new dolabellane, clavinflol C (1), three known dolabellanes, stolonidiol (2), stolonidiol-17-acetate (3), and clavinflol B (4) as well as two new secosteroids, 3β,11-dihydroxy-24-methyl-9,11-secocholest-5-en-9,23-dione (5) and 3β,11-dihydroxy-24-methylene-9,11-secocholest-5-en-9,23-dione (6). All six compounds show less cytotoxicity than those of known proteasome inhibitors, bortezomib and MG132. In summary, the high-content measurements of control inhibitors, bortezomib and MG132, manifest the highest ratio >2 in high-content measurement. Of the isolated compounds, 2 and 5 showed higher activity, followed by 3 and 6, and then 1 and 4 exhibited moderate inhibition.

scholarly journals Characterization of platinum(II) complexes exhibiting inhibitory activity against the 20S proteasome

2020 ◽  
Vol 7 (8) ◽  
pp. 200545
Author(s):  
Tatsuto Kiwada ◽  
Hiromu Katakasu ◽  
Serina Okumura ◽  
Akira Odani
Keyword(s):  
Inhibitory Activity ◽  
Chemical Structure ◽  
Competitive Inhibition ◽  
Proteasome Inhibitors ◽  
Platinum Complex ◽  
Platinum Complexes ◽  
Binding Mode ◽  
Structure Activity Relationships ◽  
Structure Activity

Proteasome inhibitors are useful for biochemical research and clinical treatment. In our previous study, we reported that the 4N-coordinated platinum complexes with anthracenyl ring and heterocycle exhibited proteasome-inhibitory activity. In the present study, the structure–activity relationships and characterization of these complexes were determined for the elucidation of the role of aromatic ligands. Lineweaver–Burk analysis revealed that the chemical structure of heterocycles affects the binding mode of platinum complexes. Platinum complexes with anthracenyl ring and pyridine showed competitive inhibition, although platinum complexes with anthracenyl ring and phenanthroline showed non-competitive inhibition. The structure–activity relationships demonstrated that anthracenyl moiety plays a crucial role in proteasome-inhibitory activity. The platinum complexes with naphthyl or phenyl rings exhibited lower inhibitory activities than the platinum complex with anthracenyl ring. The reactivity with N-acetylcysteine varied according to the chemical structure of complexes.

PROTEASOME INHIBITION IN MULTIPLE MYELOMA: Therapeutic Implication

2005 ◽  
Vol 45 (1) ◽  
pp. 465-476 ◽  
Author(s):  
Dharminder Chauhan ◽  
Teru Hideshima ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Protein Translation ◽  
26S Proteasome ◽  
Intracellular Protein ◽  
Cycle Growth ◽  
Intracellular Protein Degradation ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Normal cellular functioning requires processing of proteins regulating cell cycle, growth, and apoptosis. The ubiquitin-proteasome pathway (UBP) modulates intracellular protein degradation. Specifically, the 26S proteasome is a multienzyme protease that degrades misfolded or redundant proteins; conversely, blockade of the proteasomal degradation pathways results in accumulation of unwanted proteins and cell death. Because cancer cells are more highly proliferative than normal cells, their rate of protein translation and degradation is also higher. This notion led to the development of proteasome inhibitors as therapeutics in cancer. The FDA recently approved the first proteasome inhibitor bortezomib (Velcade™), formerly known as PS-341, for the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Ongoing studies are examining other novel proteasome inhibitors, in addition to bortezomib, for the treatment of MM and other cancers.

scholarly journals Beclin 1 Enhances Proteasome Inhibition-Mediated Cytotoxicity of Thyroid Cancer Cells in Macroautophagy-Independent Manner

2013 ◽  
Vol 98 (2) ◽  
pp. E217-E226 ◽  
Author(s):  
Hai-Yan Zhang ◽  
Zhen-Xian Du ◽  
Xin Meng ◽  
Zhi-Hong Zong ◽  
Hua-Qin Wang
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Essential Gene ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Beclin 1 ◽  
Independent Manner ◽  
Ubiquitin Proteasome ◽  
Thyroid Cancer Cells

Abstract Context: The ubiquitin–proteasome system and macroautophagy are two major pathways for intracellular protein degradation. Emerging lines of evidence have shown that blockade of ubiquitin–proteasome system by proteasome inhibitors activates macroautophagy. Objective: The purpose of this study was to determine the involvement of autophagy essential gene Beclin 1 in cytotoxicity of thyroid cancer cells mediated by proteasome inhibitors. Design: Autophagy was measured by acidic-trophic dye staining and EGF-LC3 distribution using fluorescence microscopy, as well as LC3-II transition using Western blot. To ascertain the effect of Beclin 1, cells were transfected with Beclin 1 plasmid or shRNA against Beclin 1. Cell viability and apoptotic cells were measured using MTT assay and flow cytometry, respectively. Results: Proteasome inhibitors decreased Beclin 1 expression. In addition, treatment with PI3K inhibitors 3-MA or wortmannin, as well as knockdown of Beclin 1 expression, was unable to affect autophagic responses mediated by proteasome inhibitors. Overexpression of Beclin 1 enhanced proteasome inhibitor–mediated cytotoxicity of thyroid cancer cells via suppression of survivin. Conclusions: Proteasome inhibitors cause Beclin 1–independent macroautophagic responses of thyroid cancer cells in a Beclin 1–independent manner. Beclin 1 possesses autophagy-independent antitumoral effects upon exposure of thyroid cancer cells to proteasome inhibitors.

Drug discovery and assay development in the ubiquitin–proteasome system

2010 ◽  
Vol 38 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Celia R. Berkers ◽  
Huib Ovaa
Keyword(s):  
Proteasome Inhibitor ◽  
Clinical Success ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Clinical Use ◽  
Normal Cells ◽  
Clinical Resistance ◽  
Ubiquitin Proteasome ◽  
New Strategies

The observation that tumour cells are more sensitive to pharmacological inhibition of the proteasome than normal cells has led to the development of the proteasome inhibitor bortezomib. To date, this is the only proteasome inhibitor that has been approved for clinical use. The clinical success of bortezomib, combined with the occurrence of adverse effects and the development of clinical resistance against this compound, has initiated the development of a broad range of second-generation proteasome inhibitors as well as of assays that can be used to establish a relationship between the extent and type of proteasome inhibition and the effectiveness of a particular drug. In the present paper, we discuss new strategies that may be used in the future to overcome drug resistance and to broaden the use of proteasome inhibitors for the treatment of both cancer and infectious and autoimmune disease.

The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition

Blood ◽  
2009 ◽  
Vol 113 (13) ◽  
pp. 3040-3049 ◽  
Author(s):  
Giada Bianchi ◽  
Laura Oliva ◽  
Paolo Cascio ◽  
Niccolò Pengo ◽  
Francesca Fontana ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Proteasome Activity ◽  
Critical Determinant ◽  
Highly Sensitive ◽  
Ubiquitin Proteasome ◽  
Different Levels ◽  
Free Ubiquitin

Abstract Proteasome inhibitors (PIs) are effective against multiple myeloma (MM), but the mechanisms of action and bases of individual susceptibility remain unclear. Recent work linked PI sensitivity to protein synthesis and proteasome activity, raising the question whether different levels of proteasome expression and workload underlie PI sensitivity in MM cells (MMCs). Exploiting human MM lines characterized by differential PI sensitivity, we report that highly sensitive MMCs express lower proteasome levels and higher proteasomal workload than relatively PI-resistant MMCs, resulting in the accumulation of polyubiquitinated proteins at the expense of free ubiquitin (proteasome stress). Manipulating proteasome expression or workload alters apoptotic sensitivity to PI, demonstrating a cause-effect relationship between proteasome stress and apoptotic responses in MMCs. Intracellular immunostaining in primary, patient-derived MMCs reveals that polyubiquitinated proteins hallmark neoplastic plasma cells, in positive correlation with immunoglobulin (Ig) content, both intra- and interpatient. Moreover, overall proteasome activity of primary MMCs inversely correlates with apoptotic sensitivity to PI. Altogether, our data indicate that the balance between proteasome workload and degradative capacity represents a critical determinant of apoptotic sensitivity of MMCs to PI, potentially providing a framework for identifying indicators of responsiveness and designing novel combination therapies.

scholarly journals Proteasome inhibition in multiple myeloma: lessons for other cancers

2020 ◽  
Vol 318 (3) ◽  
pp. C451-C462 ◽  
Author(s):  
Paula Saavedra-García ◽  
Francesca Martini ◽  
Holger W. Auner
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
26S Proteasome ◽  
Cellular Functions ◽  
Glucose And Lipid Metabolism ◽  
Ubiquitin Proteasome ◽  
Cancer Multiple

Cellular protein homeostasis (proteostasis) depends on the controlled degradation of proteins that are damaged or no longer required by the ubiquitin-proteasome system (UPS). The 26S proteasome is the principal executer of substrate-specific proteolysis in eukaryotic cells and regulates a myriad of cellular functions. Proteasome inhibitors were initially developed as chemical tools to study proteasomal function but rapidly became widely used anticancer drugs that are now used at all stages of treatment for the bone marrow cancer multiple myeloma (MM). Here, we review the mechanisms of action of proteasome inhibitors that underlie their preferential toxicity to MM cells, focusing on endoplasmic reticulum stress, depletion of amino acids, and effects on glucose and lipid metabolism. We also discuss mechanisms of resistance to proteasome inhibition such as autophagy and metabolic rewiring and what lessons we may learn from the success and failure of proteasome inhibition in MM for treating other cancers with proteostasis-targeting drugs.

scholarly journals Proteasome Inhibitors as a Possible Therapy for SARS-CoV-2

2020 ◽  
Vol 21 (10) ◽  
pp. 3622 ◽  
Author(s):  
Lucia Longhitano ◽  
Daniele Tibullo ◽  
Cesarina Giallongo ◽  
Giacomo Lazzarino ◽  
Nicola Tartaglia ◽  
...  
Keyword(s):  
Proteasome Inhibitors ◽  
Immunological Response ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Additional Tool ◽  
Inflammatory Conditions ◽  
Oxygen Administration ◽  
Global Pandemic ◽  
Therapeutic Guidelines ◽  
Ubiquitin Proteasome

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.

Proteasome inhibitors as therapeutics

2005 ◽  
Vol 41 ◽  
pp. 205-218
Author(s):  
Constantine S. Mitsiades ◽  
Nicholas Mitsiades ◽  
Teru Hideshima ◽  
Paul G. Richardson ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Drug Class ◽  
Proteasome Inhibitors ◽  
Cell Cycle Regulators ◽  
Current State ◽  
Intracellular Mechanism ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Hodgkin's Lymphomas ◽  
Clinical Research Data

The ubiquitin–proteasome pathway is a principle intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies, because of the pleiotropic cell-cycle regulators and modulators of apoptosis that are controlled by proteasome function. In this chapter, we review the current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma. Particular emphasis is placed on the pre-clinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and a appraisal of possible uses in other haematological malignancies, such non-Hodgkin's lymphomas.

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