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Nuclear Factor Kappa-B: Bridging Inflammation and Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Mohammad Aslam Khan, Girijesh Kumar Patel, Haseeb Zubair, Nikhil Tyagi, Shafquat Azim, Seema Singh, Aamir Ahmad, Ajay Pratap Singh
Intracellular proteins can be degraded by ubiquitin proteasome pathway and it has been found that proteasome inhibitors possess anticancer property. These inhibitors are able to inhibit the degradation of IκB, resulting in cytoplasmic retention of NF-κB. Experimental evidences have suggested that the 26S proteasome inhibitor, bortezomib, exhibits anti-tumor activity against wide variety of cancers [161, 162]. In the year 2008, U.S. FDA approved bortezomib for the treatment of multiple myeloma (MM) patients. Combined treatment of bortezomib and irinotecan has been shown to inhibit NF-xB activation, and induce apoptosis in pancreatic cancer cells [163]. Additionally, it has been found that bortezomib enhances therapeutic efficiency of gemcitabine in the mouse model of pancreatic cancer [164]. Another proteasome inhibitor, MG132, has been shown to block NF-κB activation resulting in diminished resistance against gemcitabine [165]. It has been also shown that MG132, along with anthracycline idarubicin, inhibited constitutive NF-κB and induced apoptosis in leukemic stem cells, without affecting normal hematopoietic stem cells [166]. However, studies have also shown that bortezomib/MG132 treatment could activate NF-κB in MM and endometrial cancer, which may suggest that anti-tumor activity of these inhibitors are not associated just with the inhibition of NF-κB [167].
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.
Mechanisms of Fibril Formation and Cellular Response
Published in Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin, XIth International Symposium on Amyloidosis, 2007
Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin
proteasome. On the other hand, the intracellular V30M TTR level was slightly increased by MG132 treatment, indicating that this amyloidogenic variant might be partially targeted to ERAD. Corresponding to the intracellular levels, higher amount of V30M TTR was secreted into the medium. But compared to the effect of MG132 on V30M TTR, the effect of the proteosome inhibitor on intracellular V30M M-TTR was remarkable. In MG132-treated cells, the relative amount of intracellular V30M M-TTR was two-fold higher than in untreated cells. Since this monomeric variant TTR was incapable of being secreted, it is plausible to assume that it was degraded in the absence of a proteasome inhibitor.
Decrease in MAP3Ks expression enhances the cell death caused by hyperthermia
Published in International Journal of Hyperthermia, 2022
Atsushi Enomoto, Takemichi Fukasawa, Hiroshi Terunuma, Keiichi Nakagawa, Ayumi Yoshizaki, Shinichi Sato, Kiyoshi Miyagawa
Thermal stress also causes protein unfolding [3]. These unfolded proteins are either refolded via molecular chaperones or are broken down, if the protein structure cannot be rescued [1]. We examined the two potential pathways by which heat-induced degradation occurs, namely the ubiquitin–proteasome pathway and calpain degradation. The addition of MG132, a commonly used 26S proteasome inhibitor, partially suppressed the heat-induced degradation of TAK1 and MEKK2 (Figure 2(C)). Another calpain inhibitor, ALLN, also significantly reversed the heat-induced degradation of TAK1 and MEKK2. However, neither MG132 nor ALLN rescued the degradation of RAF1 after heat treatment. These findings suggested that heat-induced reduction in TAK1 and MEKK2 levels mainly occur via the protein degradation pathway; however, the reduction in the RAF1 level can be attributed to transcriptional downregulation and protein lability.
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.
Design, synthesis, and in vitro evaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Thomas S. Corrigan, Leilani M. Lotti Diaz, Sarah E. Border, Steven C. Ratigan, Kayla Q. Kasper, Daniel Sojka, Pavla Fajtova, Conor R. Caffrey, Guy S. Salvesen, Craig A. McElroy, Christopher M. Hadad, Özlem Doğan Ekici
Compounds 3, 4 and 5 are designed to target the β5, chymotrypsin-like (CT-L) active site of the human 20S proteasome, and thus are based on the ideal tripeptidyl sequence Leu-Leu-Leu51. To our knowledge, this is the first study where a chemical electrophilic warhead bearing an aza-P1 residue was designed and tested with the proteasome. Compounds 3, 4 and 5 showed inhibition in the mid-µM range, suggesting that the proteasome active site can actually tolerate the aza-modification at the P1 position (Table 1). Inhibition rates by the aldehyde 3 and ketones 4 and 5 seemed fairly close with the aldehyde 3 being slightly more potent with an IC50 value of 9.02 µM. The benzyl group of the ketone inhibitor 5 was well accommodated at the prime site for this warhead motif with an IC50 value of 10.11 µM, allowing further derivatisation on the aromatic ring for more potency and specificity. The overall performance of our compounds, particularly compound 3, can be directly compared to the commercially available aldehyde inhibitor MG132 (Cbz-Leu-Leu-Leu-CHO). MG132 is a very potent, but non-selective, proteasome inhibitor. In our assay, we have determined the Ki value of MG132 of the β5, chymotrypsin-like (CT-L) active site of the 20S proteasome as 14.28 ± 3.06 nM. This value compares well with the previously reported Ki values of MG132 as 2–4 nM52, “few nanomolar”53, and of the close analog MG115 (Cbz-Leu-Leu-Nle-CHO) as 21 nM54 using the same substrate Suc-LLVY-AMC as in our assay.