Proteasome Inhibitor Drugs

2020 ◽  
Vol 60 (1) ◽  
pp. 457-476 ◽  
Author(s):  
Lloyd D. Fricker

Proteasomes are large, multicatalytic protein complexes that cleave cellular proteins into peptides. There are many distinct forms of proteasomes that differ in catalytically active subunits, regulatory subunits, and associated proteins. Proteasome inhibitors are an important class of drugs for the treatment of multiple myeloma and mantle cell lymphoma, and they are being investigated for other diseases. Bortezomib (Velcade) was the first proteasome inhibitor to be approved by the US Food and Drug Administration. Carfilzomib (Kyprolis) and ixazomib (Ninlaro) have recently been approved, and more drugs are in development. While the primary mechanism of action is inhibition of the proteasome, the downstream events that lead to selective cell death are not entirely clear. Proteasome inhibitors have been found to affect protein turnover but at concentrations that are much higher than those achieved clinically, raising the possibility that some of the effects of proteasome inhibitors are mediated by other mechanisms.

2021 ◽  
Vol 11 ◽  
Author(s):  
Shansa Pranami E. Jayaweera ◽  
Sacheela Prasadi Wanigasinghe Kanakanamge ◽  
Dharshika Rajalingam ◽  
Gayathri N. Silva

The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by controlling the levels of key regulatory proteins such as cyclins and caspases in both normal and tumor cells. However, compared to normal cells, cancer cells are more dependent on the ubiquitin proteasome pathway (UPP) due to the accumulation of proteins in response to uncontrolled gene transcription, allowing proteasome to become a potent therapeutic target for human cancers such as multiple myeloma (MM). Up to date, three proteasome inhibitors namely bortezomib (2003), carfilzomib (2012) and ixazomib (2015) have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed and/or refractory MM. This review mainly focuses on the biochemical properties, mechanism of action, toxicity profile and pivotal clinical trials related to carfilzomib, a second-generation proteasome inhibitor that binds irreversibly with proteasome to overcome the major toxicities and resistance associated with bortezomib.


Biomolecules ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 51
Author(s):  
Jianhao Liu ◽  
Ruogang Zhao ◽  
Xiaowen Jiang ◽  
Zhaohuan Li ◽  
Bo Zhang

Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in recent years, different BTZ-based drug delivery systems have been evaluated. In this review, we firstly discussed the functions of proteasome inhibitors and their mechanisms of action. Secondly, the properties of BTZ, as well as recent advances in both clinical and preclinical research, were reviewed. Finally, progress in research regarding BTZ-based nanoformulations was summarized.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3740-3740
Author(s):  
Liang Zhang ◽  
Jianfei Qian ◽  
Zhishuo Ou ◽  
Luhong Sun ◽  
Kejie Zhang ◽  
...  

Abstract Abstract 3740 Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor clinical outcome, thus, novel therapeutic agents are urgently needed. The proteasome inhibitors are small molecular agents which show significant anti-tumor effect in patients with relapsed/refractory MCL. Carfilzomib, an irreversible proteasome inhibitor with selectivity for the chymotrypsin-like active site, inhibits the proliferation of MCL cells in vitro, as well as the reversible proteasome inhibitor bortezomib. Unlike bortezomib, carfilzomib is good-tolerated and does not induce severe neuropathy in patients. Therefore, carfilzomib can be used in higher dose than bortezomib in vivo. Our study was undertaken to evaluate the therapeutic efficacy of carfilzomib on MCL cells both in vitro and in vivo compared with bortezomib. Four human MCL cell lines, MINO, Jeko-1, MAVER, and NCEB-1, freshly isolated primary MCL cells from the patients with relapsed/refractory MCL, were treated with carfilzomib or bortezomib. A 3H-thymidine incorporation assay showed that both carfilzomib and bortezomib displayed the same dose-dependent manner in inducing growth inhibition of the MCL cells. Similarly, flow cytometry analysis with fluorescence-labeled Annexin V and propidium iodide showed that carfilzomib induced apoptosis of MCL cells in the same dose-dependent manner with bortezomib. However, under the tolerable dose of each of the two proteasome inhibitors, they had different therapeutic effect in a MCL-bearing mouse model established in severe combined immunodeficient (SCID) mice. MINO cells (5 × 106) were inoculated subcutaneously into the right flank of SCID mice. Three weeks later, after palpable tumors developed, mice were treated intravenously with carfilzomib (5 mg/kg) on day 1 and day2, for 5 cycles, or treated intraperitoneally with bortezomib (1 mg/kg) on days 1, 4, 7 and 10, per 21 days. Tumor growth was almost abrogated after treatment with carfilzomib compared with bortezomib, and the survival time of tumor-bearing mice was significantly prolonged in the carfilzomib-treated mice versus bortezomib-treated mice. Notably, Increasing the frequency or dose of bortezomib treatment was unable because the mice were too suffered in toxicity to tolerate the treatment. Western blot analysis showed that carfilzomib induced apoptosis in caspase-dependent manner as well as bortezomib. Carfilzomib inhibited the phosphorylation of IκB, STAT3, and AKT and irreversibly blocked the release of NFκB to nuclei. In conclusion, carfilzomib displays the same anti-tumor effect and mechanism with bortezomib on MCL cells in vitro. However, carfilzomib but not bortezomib is well tolerated without severe side effect in vivo. Carfilzomib significantly inhibits tumor growth and prolongs survival indicating that carfilzomib is a potential agent in MCL chemotherapy. Disclosures: No relevant conflicts of interest to declare.


2020 ◽  
Vol 20 (6) ◽  
pp. 643-650 ◽  
Author(s):  
Mitra Korani ◽  
Shahla Korani ◽  
Elham Zendehdel ◽  
Mahmoud R. Jaafari ◽  
Thozhukat Sathyapalan ◽  
...  

Cancer is a condition where there is an uncontrolled growth of cells resulting in high mortality. It is the second most frequent cause of death worldwide. Bortezomib (BTZ) is a Proteasome Inhibitor (PI) that is used for the treatment of a variety of cancers. It is the first PI that has received the approval of the US Food and Drug Administration (FDA) to treat mantle cell lymphoma and multiple myeloma. High incidence of sideeffects, limited dose, low water solubility, fast clearance, and drug resistance are the significant limitations of BTZ. Therefore, various drug delivery systems have been tried to overcome these limitations of BTZ in cancer therapy. Nanotechnology can potentially enhance the aqueous solubility of BTZ, increase its bioavailability, and control the release of BTZ at the site of administration. The lipid-based nanocarriers, such as liposomes, solid lipid NPs, and microemulsions, are some of the developments in nanotechnology, which could potentially enhance the therapeutic benefits of BTZ.


2021 ◽  
pp. 106672
Author(s):  
Yoshiaki Kuroda ◽  
Daisuke Koyama ◽  
Jiro Kikuchi ◽  
Shigehisa Mori ◽  
Tatsuo Ichinohe ◽  
...  

2003 ◽  
Vol 1 (5) ◽  
pp. S302 ◽  
Author(s):  
O.A. O'Connor ◽  
J. Wright ◽  
C. Moskowitz ◽  
D. Straus ◽  
B. MacGregor-Cortelli ◽  
...  

2002 ◽  
Vol 20 (22) ◽  
pp. 4420-4427 ◽  
Author(s):  
Robert Z. Orlowski ◽  
Thomas E. Stinchcombe ◽  
Beverly S. Mitchell ◽  
Thomas C. Shea ◽  
Albert S. Baldwin ◽  
...  

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib (previously known as PS-341) in patients with refractory hematologic malignancies.PATIENTS AND METHODS: Patients received PS-341 twice weekly for 4 weeks at either 0.40, 1.04, 1.20, or 1.38 mg/m2, followed by a 2-week rest. The PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity.RESULTS: Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles. DLTs at doses above the 1.04-mg/m2MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In three of 10 patients receiving additional therapy, serious reversible adverse events appeared during cycle 2, including one episode of postural hypotension, one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed PS-341 induced 20S proteasome inhibition in a time-dependent manner, and this inhibition was also related to both the dose in milligrams per meter squared, and the absolute dose of PS-341. Among nine fully assessable patients with heavily pretreated plasma cell dyscrasias completing one cycle of therapy, there was one complete response and a reduction in paraprotein levels and/or marrow plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma and another with follicular lymphoma had shrinkage of nodal disease.CONCLUSION: PS-341 was well tolerated at 1.04 mg/m2on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin’s lymphoma in this study, and merits further investigation in these populations.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18727-e18727
Author(s):  
Robert Smith ◽  
Mei Xue ◽  
Natalie Dorrow ◽  
Prateesh Varughese ◽  
Cosima Hogea ◽  
...  

e18727 Background: Treatment for multiple myeloma (MM) over the past decade has significantly improved survival. In particular, 3 drug classes have altered the treatment paradigm for MM patients: proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and CD38 monoclonal antibodies (anti-CD38s). Despite these advances, the majority of patients with MM will become refractory to PIs, IMiDs, and anti-CD38s, and limited evidence indicates these patients have poor outcomes. A retrospective study in the US showed that 275 patients treated at 14 academic institutions with prior exposure to a PI, IMiD, and anti-CD38 had median overall survival of 9.2 months. The aim of this study was to evaluate real-world treatment patterns and outcomes (duration of therapy and overall survival) of patients who had been treated with a PI, IMiD, and anti-CD38 in community practices in the US. Methods: This retrospective observational study was conducted using the Integra Connect (IC) database. The IC database includes electronic health data from structured and unstructured fields from 12 community practices on the East and West Coast of the US. Adult patients with ≥2 ICD-9/ICD-10 codes for MM on at least 2 separate dates, who received MM treatment between Jan 1, 2016, and Dec 31, 2019, with treatment history that included at least one PI, one IMiD, and one anti-CD38 (triple exposed), and initiated a subsequent line of therapy (s-LOT) after becoming triple exposed, were included. Duration of length of s-LOT was defined as number of days from start of s-LOT to last-day supply of s-LOT. Overall survival was defined as the length of time from start of s-LOT through death or the date of the last office visit. Results: A total of 501 patients were included in this analysis. The median age of patients was 64.9 years; 50% were male; 50% had commercial insurance. 82.8% of patients had ECOG 0 or 1 at diagnosis and had received a median of 3 prior lines of therapy (LOTs) before initiating s-LOT. Prior to initiating s-LOT, 91% had been exposed to bortezomib, 81% to carfilzomib, 94% to lenalidomide, 82% to pomalidomide, and 100% to daratumumab. In s-LOT, 95% received treatment that included same drug or same drug class (30% received bortezomib, 48% carfilzomib, 31% lenalidomide, 47% pomalidomide, and 31% daratumumab). The median duration of s-LOT was 78 days and median survival was 10.3 months (308 days) from initiation of s-LOT. Conclusions: For triple-class exposed patients, there is a lack of consensus on the most efficacious approach to subsequent treatment. The present study shows a significant amount of retreatment with previously used agents or classes among these patients with short duration of therapy and poor survival. As has been previously noted, new strategies and agents targeting novel aspects of MM are needed to improve outcomes for these patients. Disclosures: This study (213286) was sponsored by GlaxoSmithKline.


1994 ◽  
Vol 72 (5-6) ◽  
pp. 195-201 ◽  
Author(s):  
Claude Hamelin ◽  
Benoit D'Amours ◽  
Christian Page ◽  
Young Sup Chung

Simian virus 40 (SV40) chromatin extracted from nuclei of infected monkey cells (CV1) was sedimented in neutral sucrose gradients, before and after digestion with bovine pancreatic RNase I-A or DNase I. DNA topoisomerase (TI) activity was found associated with RNase-resistant, DNase-sensitive SV40 nucleoprotein complexes. After polyacrylamide gel electrophoresis, a number of proteins with a molecular mass between 40 and 70 kDa were seen at the level of viral DNA peaks, some of which may represent catalytically active breakdown products of the TI enzyme. Large protein complexes were observed under the electron microscope in association with the viral chromosomes and appear to correspond to the SV40 DNA replication complex, including TI. Our results suggest that TI activity is indeed associated with the viral minichromosomes undergoing replication in vivo.Key words: deoxyribonucleoproteins, DNA topoisomerase, minichromosomes, ribonucleoproteins, simian virus 40, viral chromatin.


2005 ◽  
Vol 94 (12) ◽  
pp. 1203-1212 ◽  
Author(s):  
Doris Cerecedo ◽  
Dalila Martínez-Rojas ◽  
Oscar Chávez ◽  
Francisco Martínez-Pérez ◽  
Francisco García-Sierra ◽  
...  

SummaryPlatelets are dynamic cell fragments that modify their shape during activation. Utrophin and dystrophins are minor actin-binding proteins present in muscle and non-muscle cytoskeleton. In the present study, we characterised the pattern of Dp71 isoforms and utrophin gene products by immunoblot in human platelets. Two new dystrophin isoforms were found, Dp71f and Dp71d, as well as the Up71 isoform and the dystrophin-associated proteins, α and β-dystrobrevins. Distribution of Dp71d/Dp71Δ110 m, Up400/Up71 and dystrophin-associated proteins in relation to the actin cytoskeleton was evaluated by confocal microscopy in both resting and platelets adhered on glass. Formation of two dystrophin-associated protein complexes (Dp71d/Dp71Δ110 m ~DAPC and Up400/Up71~DAPC) was demonstrated by co-immunoprecipitation and their distribution in relation to the actin cytoskeleton was characterised during platelet adhesion. The Dp71d/Dp71Δ110 m ~DAPC is maintained mainly at the granulomere and is associated with dynamic structures during activation by adhesion to thrombin-coated surfaces. Participation of both Dp71d/Dp71Δ110 m ~DAPC and Up400/Up71~DAPC in the biological roles of the platelets is discussed.


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