Proteasome Regulator Marizomib (NPI-0052) Exhibits Prolonged Inhibition, Attenuated Efflux, and Greater Cytotoxicity than Its Reversible Analogs

Obaidat, Amanda; Weiss, Jeffrey; Wahlgren, Brett; Manam, Rama Rao; Macherla, Venkat R.; McArthur, Katherine; Chao, Ta-Hsiang; Palladino, Michael A.; Lloyd, G. Kenneth; Potts, Barbara C. M.; Enna, S.J.; Neuteboom, Saskia; Hagenbuch, Bruno

doi:10.1124/jpet.110.177824

Cited by 27 publications

(13 citation statements)

References 24 publications

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“…Preclinical assays revealed that the irreversible binding of marizomib to the proteasome is responsible for its slower efflux, longer duration of action and greater cytotoxicity compared with other reversible analogs of bortezomib [100]. Stable disease was observed in patients with colorectal and hepatocellular carcinoma and also other tumor types, in a Phase I trial conducted in hematological and solid tumors [101].…”

Section: Targeting the Proteasomementioning

confidence: 99%

New targeted approaches against the ubiquitin–proteasome system in gastrointestinal malignancies

Grande¹,

Earl²,

Fuentes

et al. 2012

Expert Review of Anticancer Therapy

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Section: Targeting the Proteasomementioning

confidence: 99%

New targeted approaches against the ubiquitin–proteasome system in gastrointestinal malignancies

Grande¹,

Earl²,

Fuentes

et al. 2012

Expert Review of Anticancer Therapy

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“…Since carfilzomib displays differential binding properties compared to bortezomib it has been approved by the FDA for treatment of multiple myeloma patients that have previously received two prior therapies, including bortezomib and who subsequently relapsed. Marizomib (NPI-0052), a natural product derived from the fermentation of the marine actinobacterium Salinospora (Chauhan et al, 2005), also inhibits the chymotryptic-like activity of the 20S proteasome via a similar mechanism of action to bortezomib and carfilzomib (Herndon et al, 2013;Obaidat et al, 2011;Singh et al, 2010).…”

Section: Targeting the Ups In Cancermentioning

confidence: 99%

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

Selvaraju

Mazurkiewicz

Wang

et al. 2015

Drug Resistance Updates

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The ubiquitin-proteasome system (UPS) is the primary mechanism controlling the degradation of damaged, unwanted or short-lived proteins in eukaryotic cells. In addition to protein homeostasis, the UPS has also emerged as a critical node in the regulation of signalling pathways implicated in the growth and survival of cancer cells. The absolute dependency of cancer cells on a functioning UPS has been exploited in the development of anti-cancer therapies as exemplified by development of proteasome inhibitors for the treatment of certain leukemic malignancies.Deubiquitinases (DUBs) are enzyme components of the UPS that catalyse re-editing of poly ubiquitin chains and/or removal of ubiquitin en bloc from target substrates leading to alterations in protein stability and/or downstream signalling. There is a growing recognition that targeting DUB activity may be a feasible option for the development of novel anti-cancer therapies. In particular inhibition of proteasomal cysteine DUBs (i.e. USP14 and UCHL5) has been shown to be particularly cytotoxic to cancer cells leading to the accumulation of ubiquitinated proteins and proteotoxic stress. In this review we focus on the mechanisms of action of proteasome DUB inhibitors as well as the potential of such compounds to circumvent acquired drug resistance in cancer patients.

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“…14 It is able to induce apoptosis in primary myeloma cells refractory to treatment with conventional myeloma therapies 73 and combines synergistically with bortezomib and lenalidomide in vivo. [74][75][76] ONX0912 is the only irreversible proteasome inhibitor that is orally bioavailable. It too has shown activity in myeloma cells resistant to conventional therapy and enhances tumor regression in vivo.…”

confidence: 99%

“…[74][75][76] ONX0912 is the only irreversible proteasome inhibitor that is orally bioavailable. It too has shown activity in myeloma cells resistant to conventional therapy and enhances tumor regression in vivo.…”

mentioning

confidence: 99%

DangER: protein ovERload. Targeting protein degradation to treat myeloma

Aronson¹,

Davies²

2012

Haematologica

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Myeloma is a malignancy of the antibody-producing plasma cells and, as such, these cells synthesize large quantities of unfolded or misfolded immunoglobulin. The build-up of excess protein triggers a number of downstream signal transduction cascades, including endoplasmic reticulum stress and autophagy. As a result, myeloma cells are uniquely reliant on these and other protein handling pathways for their survival. Strategies aimed at targeting this vulnerability have proved successful with the proteasome inhibitor, bortezomib, already licensed for clinical use. In addition to the proteasome, various other points within the protein handling pathways are also the subject of drug discovery projects, with some already progressing into clinical trials. These include compounds directed against heat shock proteins, the unfolded protein response and pathways both upstream and downstream of the proteasome.More recently, the role of autophagy has been recognized in myeloma. In this review, we discuss the various pathways used by myeloma cells for survival, with particular emphasis on the emerging role and conundrum of autophagy, as well as highlighting pre-clinical research on novel inhibitors targeting protein handling pathways.Key words: autophagy, proteasome, ER stress, heat-shock chaperones, unfolded protein response.Citation: Aronson LI and Davies FE. DangER: protein ovERload. Targeting protein degradation to treat myeloma. Haematologica 2012;97(8):1119-1130. doi:10.3324/haematol.2012 This is an open-access paper. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nbeen extensively reviewed and so will not be covered further here. 7,8 We aim to provide an overview of the protein handling and stress response pathways. We highlight the potential points in these pathways that can be targeted therapeutically, and review the supporting pre-clinical data. Protein handling pathwaysUnder normal conditions, the synthesis, folding and degradation of cellular proteins are balanced processes. In myeloma cells, however, the protein folding capacity of the endoplasmic reticulum (ER) is overloaded by large quantities of immunoglobulin and cells must adapt to this continual stress. 9 A close relationship with common signaling nodes therefore exists between the ubiquitin proteasome pathway, cellular stress pathways such as the unfolded protein response (UPR), heat shock response and autophagy. Ubiquitin proteasome pathwayThe main cellular pathway for the removal and destruction of proteins is the ubiquitin proteasome pathway. This involves the sequential enzymatic transfer of ubiquitin monomers onto an elongating polyubiquitin chain bound at the lysine 11 or lysine 48 residues of target proteins. 10 In the first step of this cascade, an E1 activating enzyme, typically ubiquitin activating enzyme (UAE, also known as UBA1), binds ubiquitin. A second ubiquitin monomer binds to a different site on the E1 enzyme and the first ubiquitin is transferred to an E2 ubiquitin-conjugating enzyme. The final step involves the transfer of ubiq...

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Proteasome Regulator Marizomib (NPI-0052) Exhibits Prolonged Inhibition, Attenuated Efflux, and Greater Cytotoxicity than Its Reversible Analogs

Cited by 27 publications

References 24 publications

New targeted approaches against the ubiquitin–proteasome system in gastrointestinal malignancies

New targeted approaches against the ubiquitin–proteasome system in gastrointestinal malignancies

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

DangER: protein ovERload. Targeting protein degradation to treat myeloma

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