scholarly journals Combined Effect of Bortezomib and Menadione Sodium Bisulfite on Proteasomes of Tumor Cells: The Dramatic Decrease of Bortezomib Toxicity in a Preclinical Trial

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 351 ◽  
Author(s):  
Tatiana Astakhova ◽  
Alexey Morozov ◽  
Pavel Erokhov ◽  
Maria Mikhailovskaya ◽  
Sergey Akopov ◽  
...  
Keyword(s):  
High Efficiency ◽  
Sodium Bisulfite ◽  
Proteasome Activity ◽  
26S Proteasome ◽  
Mammary Adenocarcinoma ◽  
Antitumor Drugs ◽  
Antitumor Effects ◽  
Preclinical Trial ◽  
Menadione Sodium Bisulfite

Tumor growth is associated with elevated proteasome expression and activity. This makes proteasomes a promising target for antitumor drugs. Current antitumor drugs such as bortezomib that inhibit proteasome activity have significant side effects. The purpose of the present study was to develop effective low-toxic antitumor compositions with combined effects on proteasomes. For compositions, we used bortezomib in amounts four and ten times lower than its clinical dose, and chose menadione sodium bisulfite (MSB) as the second component. MSB is known to promote oxidation of NADH, generate superoxide radicals, and as a result damage proteasome function in cells that ensure the relevance of MSB use for the composition development. The proteasome pool was investigated by the original native gel electrophoresis method, proteasome chymotrypsin-like activity—by Suc-LLVY-AMC-hydrolysis. For the compositions, we detected 10 and 20 μM MSB doses showing stronger proteasome-suppressing and cytotoxic in cellulo effects on malignant cells than on normal ones. MSB indirectly suppressed 26S-proteasome activity in cellulo, but not in vitro. At the same time, MSB together with bortezomib displayed synergetic action on the activity of all proteasome forms in vitro as well as synergetic antitumor effects in cellulo. These findings determine the properties of the developed compositions in vivo: antitumor efficiency, higher (against hepatocellular carcinoma and mammary adenocarcinoma) or comparable to bortezomib (against Lewis lung carcinoma), and drastically reduced toxicity (LD50) relative to bortezomib. Thus, the developed compositions represent a novel generation of bortezomib-based anticancer drugs combining high efficiency, low general toxicity, and a potentially expanded range of target tumors.

scholarly journals Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2

2018 ◽  
Vol 115 (32) ◽  
pp. 8155-8160 ◽  
Author(s):  
Sourav Banerjee ◽  
Chenggong Ji ◽  
Joshua E. Mayfield ◽  
Apollina Goel ◽  
Junyu Xiao ◽  
...  
Keyword(s):  
Curcuma Longa ◽  
Xenograft Model ◽  
Proteasome Inhibition ◽  
Binding Pocket ◽  
Tumor Burden ◽  
Proteasome Activity ◽  
26S Proteasome ◽  
Dual Specificity ◽  
Immunocompromised Mice

Curcumin, the active ingredient in Curcuma longa, has been in medicinal use since ancient times. However, the therapeutic targets and signaling cascades modulated by curcumin have been enigmatic despite extensive research. Here we identify dual-specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome, as a direct target of curcumin. Curcumin occupies the ATP-binding pocket of DYRK2 in the cocrystal structure, and it potently and specifically inhibits DYRK2 over 139 other kinases tested in vitro. As a result, curcumin diminishes DYRK2-mediated 26S proteasome phosphorylation in cells, leading to reduced proteasome activity and impaired cell proliferation. Interestingly, curcumin synergizes with the therapeutic proteasome inhibitor carfilzomib to induce apoptosis in a variety of proteasome-addicted cancer cells, while this drug combination exhibits modest to no cytotoxicity to noncancerous cells. In a breast cancer xenograft model, curcumin treatment significantly reduces tumor burden in immunocompromised mice, showing a similar antitumor effect as CRISPR/Cas9-mediated DYRK2 depletion. These results reveal an unexpected role of curcumin in DYRK2-proteasome inhibition and provide a proof-of-concept that pharmacological manipulation of proteasome regulators may offer new opportunities for anticancer treatment.

Applications of ROS-Induced Zr-MOFs Platform in Multimodal Synergistic Therapy

2021 ◽  
Vol 21 ◽  
Author(s):  
Qiongjie Ding ◽  
Yiwei Liu ◽  
Chuncheng Shi ◽  
Jifei Xiao ◽  
Wei Dai ◽  
...  
Keyword(s):  
Drug Delivery ◽  
High Efficiency ◽  
Tumor Therapy ◽  
Antitumor Effects ◽  
Metal Organic ◽  
Low Toxicity ◽  
Therapeutic Mechanisms ◽  
Biological Performance

Background: Metal-organic frameworks (MOFs) exhibited the adjustable aperture, high load capacities, tailorable structures, and excellent biocompatibilities that have used to be as drug delivery carries in cancer therapy. Until now, Zr-MOFs in particular combine optimal stability towards hydrolysis and postsynthetic modification with low toxicity, and are widely studied for its excellent biological performance. Introduction: This review comprises the exploration of Zr-MOFs as drug delivery devices (DDSs) with focus on various new methods, including chemotherapy (CT), photodynamic therapy (PDT), photothermal therapy (PTT), sonodynamic therapy(SDT), radiotherapy, immunotherapy, gene therapy and related combined therapies, which all generate reactive oxygen species (ROS) to achieve the high efficiency of tumor therapy. Conclusion: We described and summarized these pertinent examples of the therapeutic mechanisms and highlight the antitumor effects of their biological application both in vitro and in vivo. The perspectives on their future applications and analogous challenge of the Zr-MOFs materials are given.

scholarly journals The Phosphatase SHP-2 Activates HIF-1α in Wounds In Vivo by Inhibition of 26S Proteasome Activity

2019 ◽  
Vol 20 (18) ◽  
pp. 4404 ◽  
Author(s):  
Yvonn Heun ◽  
Katharina Grundler Groterhorst ◽  
Kristin Pogoda ◽  
Bjoern F Kraemer ◽  
Alexander Pfeifer ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Hypoxia Inducible Factor ◽  
Proteasome Activity ◽  
26S Proteasome ◽  
Mitogen Activated Protein Kinase ◽  
Hypoxic Conditions ◽  
Mitogen Activated Protein ◽  
Specific Regulation

Vascular remodeling and angiogenesis are required to improve the perfusion of ischemic tissues. The hypoxic environment, induced by ischemia, is a potent stimulus for hypoxia inducible factor 1α (HIF-1α) upregulation and activation, which induce pro-angiogenic gene expression. We previously showed that the tyrosine phosphatase SHP-2 drives hypoxia mediated HIF-1α upregulation via inhibition of the proteasomal pathway, resulting in revascularization of wounds in vivo. However, it is still unknown if SHP-2 mediates HIF-1α upregulation by affecting 26S proteasome activity and how the proteasome is regulated upon hypoxia. Using a reporter construct containing the oxygen-dependent degradation (ODD) domain of HIF-1α and a fluorogenic proteasome substrate in combination with SHP-2 mutant constructs, we show that SHP-2 inhibits the 26S proteasome activity in endothelial cells under hypoxic conditions in vitro via Src kinase/p38 mitogen-activated protein kinase (MAPK) signalling. Moreover, the simultaneous expression of constitutively active SHP-2 (E76A) and inactive SHP-2 (CS) in separate hypoxic wounds in the mice dorsal skin fold chamber by localized magnetic nanoparticle-assisted lentiviral transduction showed specific regulation of proteasome activity in vivo. Thus, we identified a new additional mechanism of SHP-2 mediated HIF-1α upregulation and proteasome activity, being functionally important for revascularization of wounds in vivo. SHP-2 may therefore constitute a potential novel therapeutic target for the induction of angiogenesis in ischemic vascular disease.

scholarly journals 26S Proteasome Activity Is Down-Regulated in Lung Cancer Stem-Like Cells Propagated In Vitro

PLoS ONE ◽  
2010 ◽  
Vol 5 (10) ◽  
pp. e13298 ◽  
Author(s):  
Jing Pan ◽  
Qi Zhang ◽  
Yian Wang ◽  
Ming You
Keyword(s):  
Lung Cancer ◽  
Proteasome Activity ◽  
26S Proteasome

scholarly journals HSP70-driven molecular response to the proteasome machinery inhibition is a vulnerability in cancer

2021 ◽  
Author(s):  
Magdalena Oron ◽  
Marcin Grochowski ◽  
Akanksha Jaiswar ◽  
Magdalena Nowak-Niezgoda ◽  
Malgorzata Kolos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cancer Cells ◽  
Proteasome Inhibition ◽  
Cell Types ◽  
Proteasome Activity ◽  
26S Proteasome ◽  
Molecular Response ◽  
Compensatory Mechanisms ◽  
Compensatory Response

Human neoplasias are often addicted to the cellular proteasome machinery. This has led to the development of bortezomib and carfilzomib proteasome inhibitors, approved for the treatment of multiple myeloma. Cancers, however, were found resistant to the proteasome inhibition in clinical trials, suggesting effective, cancer-specific compensatory responses. Here we employed global proteomics to determine contributions of compensatory mechanisms upon the proteasome inhibition with carfilzomib - in the cells of multiple myeloma, normal fibroblasts, and cancers of lung, colon, and pancreas. A pathway-oriented siRNA screen based on proteomics results showed that molecular chaperones, autophagy- and endocytosis-related proteins are cancer-specific vulnerabilities in combination with carfilzomib. HSP70 family chaperones HSPA1A/B were the most universal proteasome inhibition responders in the proteomes of all the studied cell types and HSPA1A/B inhibition most specifically sensitized cancer cells to carfilzomib in cell lines, patient-derived organoids and mouse xenografts. Overlap of proteomics with RNA-seq data showed that the proteasome inhibition-dependent HSPA1A/B induction in cancer cells is mainly transcription-driven and HSF1/2-dependent. Consequently, we found that a high level of HSPA1A/B mRNA is associated with a low proteasome activity in cancer patient tissues and is a risk factor in cancer patients with the low level of expression of the proteasome. Functionally, the HSPA1A/B induction does not affect a proteasome expression bounce-back upon the carfilzomib treatment, while it supports other mechanisms of the proteasome inhibition response - autophagy, unfolded protein response, and directly the 26S proteasome activity. We found that the 26S proteasome is chaperoned and protected from the inhibition with carfilzomib by HSPA1A/B assisted by DNAJB1 co-chaperone in cancer cells and using purified protein system in vitro. Thus, we define HSPA1A/B as a central player in the cellular compensatory response to the decreased proteasome activity, and the sensitive target in cancer cells with the inhibited proteasome.

AN IN-VITRO ABNORMALITY OF GLUTATHIONE METABOLISM IN ERYTHROCYTES FROM NORMAL NEWBORNS: MECHANISM AND CLINICAL SIGNIFICANCE

PEDIATRICS ◽  
1959 ◽  
Vol 23 (1) ◽  
pp. 18-32
Author(s):  
William H. Zinkham
Keyword(s):  
Whole Blood ◽  
Marked Decrease ◽  
Normal Activity ◽  
Sodium Bisulfite ◽  
Stability Test ◽  
Glutathione Metabolism ◽  
Menadione Sodium Bisulfite ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Normal Adults

When erythrocytes from a group of 66 normal Negro and white infants, 1 to 84 hours old, were incubated with acetylphenylhydrazine, a marked decrease in concentration of reduced glutathione (GSH) occurred. Concentrations of GSH in whole blood of these infants were the same or higher than those observed in normal adults. The degree of GSH instability was less marked in those infants older than 36 hours. The addition of alpha-tocopherol or plasma of adults to erythrocytes of infants did not alter the abnormal GSH stability test. Assays for activity of glucose-6-phosphate dehydrogenase were performed with erythrocytes from a group of 40 normal Negro and white newborns with an age range of 1 to 81 hours. The majority of these infants manifested abnormal GSH stability tests. Activities of the enzyme in 37 of these infants were 219.8 to 406.3 units. In a group of 38 normal adults the activities were 149.9 to 216.5 units/100 ml of erythrocytes. Three Negro male infants with activities of the enzyme less than 43.3 units were observed, and a genetic background for this deficiency of enzyme was demonstrated in the mothers of these babies. The abnormal GSH stability test in those infants with normal activity of glucose-6-phosphate dehydrogenase in erythrocytes was corrected by the addition of glucose in sufficient quantity to result in final concentrations of 30 to 160 mg/100 ml. Additional glucose had no effect on the results of the GSH stability test performed with bloods from four Negro infants with diminished activity of the enzyme. Concentrations of glucose in whole blood of infants, incubated aerobically with menadione sodium bisulfite at 37°C for 2 hours, were usually 11 mg/100 ml or less, whereas values in blood of adults ranged between 40 and 50 mg/100 ml. By determining concentrations of GSH and glucose simultaneously in blood of infants and adults after the blood had been exposed to menadione sodium bisulfite, it was found that a marked decrease in the content of GSH in erythrocytes occurred when concentrations of glucose of 10 mg/100 ml were attained. No correlation between concentrations of glucose and GSH was demonstrated when blood from a "reacting" adult was incubated with menadione sodium bisulfite. Also, when blood from a normal newborn was incubated aerobically at 37°C for 4½ hours in the absence of menadione sodium bisulfite, the concentration of GSH remained normal, even though concentrations of sugar were less than 10 mg/100 ml during the last 2 hours of incubation. It is concluded that the abnormal GSH stability test observed in most newborns can be attributed to an in-vitro deficiency of glucose. In a small percentage of Negro babies, however, this alteration of glutathione metabolism is associated with a genetically determined deficiency of activity of glucose-6-phosphate dehydrogenase. Whether or not newborns with the nongenetic type of GSH instability are unusually susceptible to the hemolytic effects of certain drugs or chemicals has not been settled. At least two infants with the inherited abnormality of metabolism of erythrocytes, however, have responded with severe hemolytic anemia when exposed to menadione sodium bisulfite and naphthalene. Even though added glucose corrects the in-vitro instability of GSH in erythrocytes of those infants with normal activity of the enzyme, the role of glucose in the evolution of hemolytic anemias occurring in the newborn period has not been determined.

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