Overview of Proteasome Inhibitor-Based Anti-cancer Therapies: Perspective on Bortezomib and Second Generation Proteasome Inhibitors versus Future Generation Inhibitors of Ubiquitin-Proteasome System

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.

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The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites

Parasitology ◽

10.1017/s003118200500747x ◽

2005 ◽

Vol 131 (1) ◽

pp. 37-44 ◽

Cited By ~ 55

Author(s):

C. LINDENTHAL ◽

N. WEICH ◽

Y.-S. CHIA ◽

V. HEUSSLER ◽

M.-Q. KLINKERT

Keyword(s):

Protein Degradation ◽

Proteasome Inhibitor ◽

Proteasome Inhibitors ◽

Protein Conjugates ◽

Anti Cancer ◽

Dividing Cells ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Further Development ◽

Specific Peptide

Protein degradation is regulated during the cell cycle of all eukaryotic cells and is mediated by the ubiquitin-proteasome pathway. Potent and specific peptide-derived inhibitors of the 20S proteasome have been developed recently as anti-cancer agents, based on their ability to induce apoptosis in rapidly dividing cells. Here, we tested a novel small molecule dipeptidyl boronic acid proteasome inhibitor, named MLN-273 on blood and liver stages of Plasmodium species, both of which undergo active replication, probably requiring extensive proteasome activity. The inhibitor blocked Plasmodium falciparum erythrocytic development at an early ring stage as well as P. berghei exoerythrocytic progression to schizonts. Importantly, neither uninfected erythrocytes nor hepatocytes were affected by the drug. MLN-273 caused an overall reduction in protein degradation in P. falciparum, as demonstrated by immunoblots using anti-ubiquitin antibodies to label ubiquitin-tagged protein conjugates. This led us to conclude that the target of the drug was the parasite proteasome. The fact that proteasome inhibitors are presently used as anti-cancer drugs in humans forms a solid basis for further development and makes them potentially attractive drugs also for malaria chemotherapy.

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Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Cancers ◽

10.3390/cancers12040902 ◽

2020 ◽

Vol 12 (4) ◽

pp. 902 ◽

Cited By ~ 1

Author(s):

Xiaonan Zhang ◽

Stig Linder ◽

Martina Bazzaro

Keyword(s):

Cancer Cells ◽

Mammalian Cells ◽

Proteasome Inhibitors ◽

Cancer Therapeutics ◽

Ubiquitin Proteasome System ◽

Cancer Therapies ◽

Catalytic Core ◽

Essential Components ◽

Ubiquitin Proteasome ◽

Ubiquitin Conjugating Enzymes

Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin–proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.

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The ubiquitin–proteasome system: opportunities for therapeutic intervention in solid tumors

Endocrine Related Cancer ◽

10.1530/erc-14-0005 ◽

2014 ◽

Vol 22 (1) ◽

pp. T1-T17 ◽

Cited By ~ 57

Author(s):

Daniel E Johnson

Keyword(s):

Solid Tumors ◽

Second Generation ◽

Proteasome Inhibitors ◽

Ubiquitin Proteasome System ◽

Therapeutic Benefit ◽

26S Proteasome ◽

Preclinical Development ◽

United States Food ◽

Ubiquitin Proteasome ◽

Us Fda

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.

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Pueraria lobata and Daidzein Reduce Cytotoxicity by Enhancing Ubiquitin-Proteasome System Function in SCA3-iPSC-Derived Neurons

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/8130481 ◽

2019 ◽

Vol 2019 ◽

pp. 1-18

Author(s):

I-Cheng Chen ◽

Kuo-Hsuan Chang ◽

Yi-Jing Chen ◽

Yi-Chun Chen ◽

Guey-Jen Lee-Chen ◽

...

Keyword(s):

Proteasome Inhibitor ◽

Caspase 3 ◽

Neurodegenerative Disorder ◽

Ubiquitin Proteasome System ◽

Proteasome Activity ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Pueraria Lobata ◽

Protein Ubiquitination ◽

Ubiquitin Proteasome

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion within the ATXN3/MJD1 gene. The expanded CAG repeats encode a polyglutamine (polyQ) tract at the C-terminus of the ATXN3 protein. ATXN3 containing expanded polyQ forms aggregates, leading to subsequent cellular dysfunctions including an impaired ubiquitin-proteasome system (UPS). To investigate the pathogenesis of SCA3 and develop potential therapeutic strategies, we established induced pluripotent stem cell (iPSC) lines from SCA3 patients (SCA3-iPSC). Neurons derived from SCA3-iPSCs formed aggregates that are positive to the polyQ marker 1C2. Treatment with the proteasome inhibitor, MG132, on SCA3-iPSC-derived neurons downregulated proteasome activity, increased production of radical oxygen species (ROS), and upregulated the cleaved caspase 3 level and caspase 3 activity. This increased susceptibility to the proteasome inhibitor can be rescued by a Chinese herbal medicine (CHM) extract NH037 (from Pueraria lobata) and its constituent daidzein via upregulating proteasome activity and reducing protein ubiquitination, oxidative stress, cleaved caspase 3 level, and caspase 3 activity. Our results successfully recapitulate the key phenotypes of the neurons derived from SCA3 patients, as well as indicate the potential of NH037 and daidzein in the treatment for SCA3 patients.

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Ubiquitination and Ubiquitin-Like Modifications in Multiple Myeloma: Biology and Therapy

Cancers ◽

10.3390/cancers12123764 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3764

Author(s):

Matthias Wirth ◽

Markus Schick ◽

Ulrich Keller ◽

Jan Krönke

Keyword(s):

Multiple Myeloma ◽

Translational Regulation ◽

Proteasome Inhibitors ◽

Ubiquitin Proteasome System ◽

Organ Damage ◽

Post Translational Modifications ◽

Damage Repair ◽

Ubiquitin Proteasome ◽

New Treatments ◽

Effective Drugs

Multiple myeloma is a genetically heterogeneous plasma cell malignancy characterized by organ damage and a massive production of (in-)complete monoclonal antibodies. Coping with protein homeostasis and post-translational regulation is therefore essential for multiple myeloma cells to survive. Furthermore, post-translational modifications such as ubiquitination and SUMOylation play key roles in essential pathways in multiple myeloma, including NFκB signaling, epigenetic regulation, as well as DNA damage repair. Drugs modulating the ubiquitin–proteasome system, such as proteasome inhibitors and thalidomide analogs, are approved and highly effective drugs in multiple myeloma. In this review, we focus on ubiquitin and ubiquitin-like modifications in the biology and current developments of new treatments for multiple myeloma.

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Regulation of Ubiquitin-Proteasome System–mediated Degradation by Cytosolic Stress

Molecular Biology of the Cell ◽

10.1091/mbc.e07-05-0487 ◽

2007 ◽

Vol 18 (11) ◽

pp. 4279-4291 ◽

Cited By ~ 58

Author(s):

Sean M. Kelly ◽

Judy K. VanSlyke ◽

Linda S. Musil

Keyword(s):

Heat Shock ◽

Secretory Pathway ◽

Proteasome Inhibitors ◽

Ubiquitin Proteasome System ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Junction Protein ◽

Ubiquitin Proteasome ◽

Gap Junction Protein ◽

Cystic Fibrosis Transmembrane

ER-associated, ubiquitin-proteasome system (UPS)-mediated degradation of the wild-type (WT) gap junction protein connexin32 (Cx32) is inhibited by mild forms of cytosolic stress at a step before its dislocation into the cytosol. We show that the same conditions (a 30-min, 42°C heat shock or oxidative stress induced by arsenite) also reduce the endoplasmic reticulum (ER)-associated turnover of disease-causing mutants of Cx32 and the cystic fibrosis transmembrane conductance regulator (CFTR), as well as that of WT CFTR and unassembled Ig light chain. Stress-stabilized WT Cx32 and CFTR, but not the mutant/unassembled proteins examined, could traverse the secretory pathway. Heat shock also slowed the otherwise rapid UPS-mediated turnover of the cytosolic proteins myoD and GFPu, but not the degradation of an ubiquitination-independent construct (GFP-ODC) closely related to the latter. Analysis of mutant Cx32 from cells exposed to proteasome inhibitors and/or cytosolic stress indicated that stress reduces degradation at the level of substrate polyubiquitination. These findings reveal a new link between the cytosolic stress-induced heat shock response, ER-associated degradation, and polyubiquitination. Stress-denatured proteins may titer a limiting component of the ubiquitination machinery away from pre-existing UPS substrates, thereby sparing the latter from degradation.

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Ubiquitin-Proteasome System Stress Sensitizes Ovarian Cancer to Proteasome Inhibitor–Induced Apoptosis

Cancer Research ◽

10.1158/0008-5472.can-05-2321 ◽

2006 ◽

Vol 66 (7) ◽

pp. 3754-3763 ◽

Cited By ~ 89

Author(s):

Martina Bazzaro ◽

Michael K. Lee ◽

Alessia Zoso ◽

Wanda L.H. Stirling ◽

Antonio Santillan ◽

...

Keyword(s):

Ovarian Cancer ◽

Proteasome Inhibitor ◽

Ubiquitin Proteasome System ◽

Ubiquitin Proteasome ◽

Induced Apoptosis

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N-Acetylcysteine in Combination with IGF-1 Enhances Neuroprotection against Proteasome Dysfunction-Induced Neurotoxicity in SH-SY5Y Cells

Parkinson s Disease ◽

10.1155/2016/6564212 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Benxu Cheng ◽

Pinki Anand ◽

Anxiu Kuang ◽

Feroz Akhtar ◽

Virginia L. Scofield

Keyword(s):

Proteasome Inhibitor ◽

Ubiquitin Proteasome System ◽

Free Radical Scavenger ◽

Parp Cleavage ◽

Radical Scavenger ◽

Nuclear Condensation ◽

Protein Ubiquitination ◽

Ubiquitin Proteasome ◽

Induced Apoptosis ◽

Human Neuronal Cells

Ubiquitin proteasome system (UPS) dysfunction has been implicated in the development of many neuronal disorders, including Parkinson’s disease (PD). Previous studies focused on individual neuroprotective agents and their respective abilities to prevent neurotoxicity following a variety of toxic insults. However, the effects of the antioxidant N-acetylcysteine (NAC) on proteasome impairment-induced apoptosis have not been well characterized in human neuronal cells. The aim of this study was to determine whether cotreatment of NAC and insulin-like growth factor-1 (IGF-1) efficiently protected against proteasome inhibitor-induced cytotoxicity in SH-SY5Y cells. Our results demonstrate that the proteasome inhibitor, MG132, initiates poly(ADP-ribose) polymerase (PARP) cleavage, caspase 3 activation, and nuclear condensation and fragmentation. In addition, MG132 treatment leads to endoplasmic reticulum (ER) stress and autophagy-mediated cell death. All of these events can be attenuated without obvious reduction of MG132 induced protein ubiquitination by first treating the cells with NAC and IGF-1 separately or simultaneously prior to exposure to MG132. Moreover, our data demonstrated that the combination of the two proved to be significantly more effective for neuronal protection. Therefore, we conclude that the simultaneous use of growth/neurotrophic factors and a free radical scavenger may increase overall protection against UPS dysfunction-mediated cytotoxicity and neurodegeneration.

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Inhibition of the Ubiquitin-Proteasome System Affects Influenza A Virus Infection at a Postfusion Step

Journal of Virology ◽

10.1128/jvi.01048-10 ◽

2010 ◽

Vol 84 (18) ◽

pp. 9625-9631 ◽

Cited By ~ 55

Author(s):

Ivy Widjaja ◽

Erik de Vries ◽

Donna M. Tscherne ◽

Adolfo García-Sastre ◽

Peter J. M. Rottier ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Rna Synthesis ◽

Proteasome Inhibitors ◽

Ubiquitin Proteasome System ◽

Bafilomycin A1 ◽

Virus Like Particle ◽

Viral Particles ◽

Removal Experiments ◽

Ubiquitin Proteasome

ABSTRACT We have demonstrated that influenza A virus (IAV) RNA synthesis depends on the ubiquitin-proteasome system. IAV replication was reduced both by proteasome inhibitors and in E36ts20 cells, which contain the thermolabile ubiquitin-activating enzyme E1. While virus entry was not affected in E36ts20 cells, the proteasome inhibitor MG132 retained viral particles in the cytoplasm. Addition-removal experiments of MG132 in combination with bafilomycin A1, a well-established inhibitor of IAV entry and fusion, showed that MG132 affected IAV infection at a postfusion step. This was confirmed by the lack of inhibition of IAV entry by proteasome inhibitors in a virus-like particle fusion assay.

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