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Proteasome and Protease Inhibitors
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
N. E. Franke, J. Vink, J. Cloos, Gertjan J. L. Kaspers
This review has mainly focused on data obtained in leukemic settings. Not many results have been published thus far regarding the different cellular pathways that are affected by proteasome inhibitors. However, when looking at data presented for other tumors, more insight can be obtained about the many ways that proteasome inhibitors induce apoptosis, including activation of JNK, stabilization of p53, Bax and Bid, and NF-κB downregulation (91). Furthermore, insights obtained in MM studies can give directions to future research regarding proteasome inhibition in leukemia. For instance, when focusing on the effect of proteasome inhibitors and the more traditional glucocorticoids (GC), Richardson et al. showed in relapsed and refractory MM that bortezomib was more efficacious than high-dose dexamethasone, resulting in a longer time to progression and a higher overall response rate (12). In vitro, bortezomib could induce apoptosis in dexamethasone-resistant MM cell lines and MM patient cells (10). Previously, Chandra et al. already showed that proteasome inhibitors lactacystin and MG-132 could induce apoptosis in both GC-sensitive and -resistant cells (63). These results make it worthwhile to investigate the effects of proteasome inhibitors in combination with the commonly used GC in leukemia and NHL.
Micronutrients in the Prevention and Improvement of the Standard Therapy for Alzheimer’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Proteasomes play an important role in regulating certain transcriptional factors by splicing inactive peptide fragments into active ones. Proteasomes also play a crucial role in the degradation of ubiquitin-conjugated abnormal proteins that could be toxic to neurons. Therefore, inhibition of proteasome in neurons can cause neurodegeneration. Indeed, the role of proteasome inhibition has been proposed for the degeneration of neurons in AD brains.14,198 In our study, inhibition of proteasome activity by lactacystin causes rapid degeneration and death neurons in culture.199 Several factors can inhibit proteasome activity. They include increased oxidative stress, defects in ubiquitin conjugation enzymes,36 mutation in ubiquitin,200 and beta-amyloid.198
The mitotic phase of spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
The requirement of protein degradation or UPS in the regulation of spermatogonia came from two studies that employed Rattus and Drosophila as model systems. The study in Drosophila has used an unbiased large-scale RNAi screening approach to identify genes involved in male germline stem cells maintenance and differentiation. Complex analysis of the screening result has revealed the genes involved in protein synthesis and degradation,75 suggesting the involvement of UPS in the process. The study in Rattus has shown that the RA-induced differentiation in gonocytes can be blocked by proteasome inhibitors lactacystin or bortezomib, indicating the requirement of proteasome activity during gonocyte differentiation.76 Gene array analysis comparing the expression profile of UPS genes in gonocytes and spermatogonia isolated from neonatal testis has identified 205 UPS genes. Among them, 28 genes showed differential expression in gonocyte versus spermatogonia. Intriguingly, genes encoding ubiquitinating enzymes have been demonstrated to have higher expression in the gonocytes whereas those encoding for deubiquitinating enzymes have higher expression in spermatogonia,76 suggesting the involvement of UPS in the establishment of spermatogonia.
Small molecules as kinetoplastid specific proteasome inhibitors for leishmaniasis: a patent review from 1998 to 2021
Published in Expert Opinion on Therapeutic Patents, 2022
Mohd Imran, Shah Alam Khan, Ahmed Subeh Alshrari, Mahmoud Mudawi Eltahir Mudawi, Mohammed Kanan Alshammari, Aishah Ali Harshan, Noufah Aqeel Alshammari
Lactacystin is a natural compound that was isolated in 1991 from the Streptomyces genus, whereas MG-132 is a synthetic peptide aldehyde that was reported in 1994 [42,43]. WO9810779A1 claims a method for treating leishmaniasis utilizing a proteasome inhibitor lactacystin (Figure 4) and MG-132 (Figure 5) along with other compounds (desmethyl lactacystin, clasto-lactacystin dihydroxy acid ss-lactone, decarboxylactacystin, MG-306, MG-309, MG-369, and MG-385) [44]. The inventors of WO9810779A1 [44] believed it to be the first patent application that disclosed the importance of proteasome inhibitors to treat protozoan parasitic diseases. The patent application reported an IC50 value of 1–2 µM for lactacystin and MG-132 against the protozoan proteasome. It also states that clasto-lactacystin dihydroxy acid is an inactive analog of lactacystin. Recent studies have also demonstrated the proteasome inhibitory potential of lactacystin (IC50 = 4.8 µM) and MG-132 (IC50 = 0.1–0.53 µM) [43,44] against human proteasome. However, no clinical trial studies have been found at the https://clinicaltrials.gov website using the terms lactacystin and MG-132.
Preadministration of high-dose alpha-tocopherol improved memory impairment and mitochondrial dysfunction induced by proteasome inhibition in rat hippocampus
Published in Nutritional Neuroscience, 2021
Ali Nesari, Mohammad Taghi Mansouri, Mohammad Javad Khodayar, Mohsen Rezaei
lactacystin is the most specific known naturally occurring membrane-permeable inhibitor of the proteasome [50]. Lactacystin was delivered into the hippocampus 1 h subsequent to training and the results revealed an impairment in the long-term memory 24 h later. As shown in Figure 2, in the passive avoidance test, latency times among the αT-treated groups and lactacystin received group were not different during training trials (P < 0.05). The results revealed a significant difference for latency time in the αT-treated groups. The step-through latency of lactacystin received rats was significantly shorter than that of the control group (P < 0.05). Moreover, the shorter step-through latencies induced by lactacystin were improved by αT-treatments at 200 mg/kg (P < 0.05) but not at 60 mg/kg (P < 0.05) versus the control group.
Cell assay for the identification of amyloid inhibitors in systemic AA amyloidosis
Published in Amyloid, 2019
Ioana Puscalau-Girtu, Judith S. Scheller, Stephanie Claus, Marcus Fändrich
Finally, we tested 15 compounds targeting different components of the cellular quality control machinery. We studied the effect of five proteasome inhibitors (bortezomib, ixazomib, carlfilzomib, MG-132 and lactacystin), two protease inhibitors (pepstatin A and E-64-d), three modulators of the unfolded protein response (1-NM-PP1, sunitinib and guanabenz), three inhibitors of molecular chaperone systems (geldanamycin, VER-155008 and BIX), as well as two autophagy modulators (wortmannin, rapamycin) (Figure 4). In case of the tested proteasome inhibitors: bortezomib, ixazomib, carlfilzomib and MG-132, we found a progressively reduced amyloid load as well as MTT signal, indicating that the toxic effect prevented the cells from forming amyloid. By contrast, lactacystin led to an increased amyloid load in our assay and did not reduce, for most of the tested concentrations, the cell viability, as judged by the MTT signal. No effect on amyloid load and MTT signal was seen with the protease inhibitors pepstatin A and E-64-d. Treatment with modulators of the unfolded protein response or of molecular chaperones resulted in a reduced amyloid formation at high compound concentrations, which correlated with the effect of these compounds in the MTT assay. In the case of autophagy modulators, we did not observe a remarkable reduction of the amyloid load or of the MTT signal with rapamycin. By contrast, wortmannin, even though it progressively reduced the measured MTT signal at higher concentrations, it drastically diminished the amyloid load at all tested concentrations, in such a way that the lowest wortmannin concentration shows a substantial reduction in amyloid formation, while little to no effect on the MTT measurement.