Development of Proteasome Inhibitors as Therapeutic Drugs

Pellom, Samuel T.; Shanker, Anil

doi:10.4172/2155-9899.s5-005

Cited by 24 publications

(23 citation statements)

References 35 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The two FDA-approved proteasome inhibitors, bortezomib and carfilzomib, both target the core proteolytic subunits PSMB5, PSMB6, and PSMB7 (38). The noncatalytic subunit PSMB4 represents a novel potential target as it plays an important role in regulating the assembly of the proteasome (28,29), and, thus, by inhibiting its function and proteasome assembly one could potentially prevent the catalytic activity of all three proteolytic subunits.…”

Section: Discussionmentioning

confidence: 99%

Comparative Oncogenomics Identifies PSMB4 and SHMT2 as Potential Cancer Driver Genes

Lee¹,

Haverty²,

Li³

et al. 2014

Cancer Research

133

106

View full text Add to dashboard Cite

Cancer genomes maintain a complex array of somatic alterations required for maintenance and progression of the disease, posing a challenge to identify driver genes among this genetic disorder. Toward this end, we mapped regions of recurrent amplification in a large collection (n ¼ 392) of primary human cancers and selected 620 genes whose expression is elevated in tumors. An RNAi loss-of-function screen targeting these genes across a panel of 32 cancer cell lines identified potential driver genes. Subsequent functional assays identified SHMT2, a key enzyme in the serine/glycine synthesis pathway, as necessary for tumor cell survival but insufficient for transformation. The 26S proteasomal subunit, PSMB4, was identified as the first proteasomal subunit with oncogenic properties promoting cancer cell survival and tumor growth in vivo. Elevated expression of SHMT2 and PSMB4 was found to be associated with poor prognosis in human cancer, supporting the development of molecular therapies targeting these genes or components of their pathways. Cancer Res; 74(11); 3114-26. Ó2014 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Comparative Oncogenomics Identifies PSMB4 and SHMT2 as Potential Cancer Driver Genes

Lee¹,

Haverty²,

Li³

et al. 2014

Cancer Research

133

106

View full text Add to dashboard Cite

show abstract

“…It plays a vital role in degrading most short-lived intra-cellular proteins that regulate a wide spectrum of events in the cell such as cell cycle, cell differentiation, cell death, DNA repair, transcription, signal transduction, morphogenesis, metabolism and antigen (Ag) presentation. The proteasome functions as the main nonlysosomal endoprotease enzyme complex within the nucleus and cytoplasm of all eukaryotic cells in order to eliminate damaged and abnormal proteins to ensure intracellular protein quality [1]. …”

Section: The Ubiquitin-proteasome System and Its Physiologic Relevancementioning

confidence: 99%

Modulatory Effects of Bortezomib on Host Immune Cell Functions

et al. 2015

View full text Add to dashboard Cite

Bortezomib is an inhibitor of the ubiquitin-proteasome proteolytic pathway responsible for intracellular protein turnover. Cellular proteins controlled by this pathway represent a diverse group of potential therapeutic targets, particularly in cancer cells, which exploit this proteasomal pathway to promote their growth and diminish apoptosis. Along with inhibiting the proteasome and thus sensitizing tumor cells to apoptosis, bortezomib may also have multiple effects on the host immune responses. This review summarizes the effects that bortezomib may play on immune cell subsets in various disease states in modifying lymphocyte receptors, ligands, the expression of various cytokines and chemokines and their downstream signaling. We also propose steps that can be taken to refine combinatorial strategies that include bortezomib to improve current immunotherapeutic approaches.

show abstract

“…3 Of the 55 most lethal genes identified, functional testing in HMCLs and non-MM cell lines indicated that proteasome subunits (A1, A3, A4, A6, C3, C4 and C5), MCL1, RRM1, USP8, TNK2, CKAP5, IK, KIF11, WBSCR22 and XPO1 are selectively vulnerable in myeloma. 3 Proteasome inhibitors have been developed and are commonly used in the clinic, 4 however, drugs that target the other potentially interesting therapeutic targets are not yet available.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276

et al. 2013

View full text Add to dashboard Cite

RNA interference screening identified XPO1 (exportin 1) among the 55 most vulnerable targets in multiple myeloma (MM). XPO1 encodes CRM1, a nuclear export protein. XPO1 expression increases with MM disease progression. Patients with MM have a higher expression of XPO1 compared with normal plasma cells (P<0.04) and to patients with monoclonal gammopathy of undetermined significance/smoldering MM (P< 0.0001). The highest XPO1 level was found in human MM cell lines (HMCLs). A selective inhibitor of nuclear export compound KPT-276 specifically and irreversibly inhibits the nuclear export function of XPO1. The viability of 12 HMCLs treated with KTP-276 was significantly reduced. KPT-276 also actively induced apoptosis in primary MM patient samples. In gene expression analyses, two genes of probable relevance were dysregulated by KPT-276: cell division cycle 25 homolog A (CDC25A) and bromodomain-containing protein 4 (BRD4), both of which are associated with c-MYC pathway. Western blotting and reverse transcription-PCR confirm that c-MYC, CDC25A and BRD4 are all downregulated after treatment with KPT-276. KPT-276 reduced monoclonal spikes in the Vk*MYC transgenic MM mouse model, and inhibited tumor growth in a xenograft MM mouse model. A phase I clinical trial of an analog of KPT-276 is ongoing in hematological malignancies including MM.

show abstract

Development of Proteasome Inhibitors as Therapeutic Drugs

Cited by 24 publications

References 35 publications

Comparative Oncogenomics Identifies PSMB4 and SHMT2 as Potential Cancer Driver Genes

Comparative Oncogenomics Identifies PSMB4 and SHMT2 as Potential Cancer Driver Genes

Modulatory Effects of Bortezomib on Host Immune Cell Functions

Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276

Contact Info

Product

Resources

About