Proteasome inhibitors in cancer therapy

Manasanch, Elisabet E.; Orłowski, Robert Z.

doi:10.1038/nrclinonc.2016.206

Cited by 762 publications

(739 citation statements)

References 142 publications

(162 reference statements)

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“…In fact, another proteasome inhibitor, bortezomib, was approved by the FDA. However, since bortezomib suppresses the degradation of all substrates in the proteasome system, it is highly toxic [45]. RA190 only blocks the degradation of specific substrates regulated by ADRM1.…”

Section: Discussionmentioning

confidence: 99%

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis

Wang

Zheng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC. Methods: The expression of ADRM1 and its prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models. Results: ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models. Conclusions: Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment.

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Section: Discussionmentioning

confidence: 99%

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis

Wang

Zheng

et al. 2018

Cell Physiol Biochem

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“…Other small-molecule compounds that phosphorylate eIF2α in vivo and reduce tumor growth are known to be well tolerated, such as eicosapentaenoic acid, a main component of fish oils [42]. Proteasome inhibitors, which induce robust eIF2α phosphorylation, are used extensively in MM and other cancers with manageable toxicity profiles [72]. The specificity of HRI activators to induce eIF2α phosphorylation without promoting oxidative stress or broadly activating eIF2α kinases may be helpful for improving the toxicity profile of these drugs compared to stress-targeting agents in development [48,49].…”

Section: Expert Opinionmentioning

confidence: 99%

The eIF2-alpha kinase HRI: a potential target beyond the red blood cell

Burwick

Aktas

2017

Expert Opinion on Therapeutic Targets

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Introduction The eIF2α kinase heme-regulated inhibitor (HRI) is one of four well-described kinases that phosphorylate eIF2α in response to various cell stressors, resulting in reduced ternary complex formation and attenuation of mRNA translation. Although HRI is well known for its role as a heme sensor in erythroid progenitors, pharmacologic activation of HRI has been demonstrated to have anti-cancer activity across a wide range of tumor sub-types. Here, the potential of HRI activators as novel cancer therapeutics is explored. Areas covered We provide an introduction to eIF2 signaling pathways in general, and specifically review data on the eIF2α kinase HRI in erythroid and non-erythroid cells. We review aspects of targeting eIF2 signaling in cancer and highlight promising data using HRI activators against tumor cells. Expert opinion Pharmacologic activation of HRI inhibits tumor growth as a single agent without appreciable toxicity in vivo. The ability of HRI activators to provide direct and sustained eIF2α phosphorylation without inducing oxidative stress or broad eIF2α kinase activation may be especially advantageous for tolerability. Combination therapy with established therapeutics may further augment anti-cancer activity to overcome disease resistance.

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“…In general, the β 5 subunits of both forms of proteasome are considered, mostly by pharmaceutical companies, as the main targets in the development of therapeutic agents . Here, the set of peptide aldehydes was tested against the β 5c (Figure A) and β 5i subunits (Figure B, and Table ).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of human constitutive 20S proteasome and 20S immunoproteasome with novel N‐terminally modified peptide aldehydes and their antitumor activity

et al. 2018

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The conversion of primary structures of novel, highly selective and sensitive, internally quenched peptide substrates of the human 20S proteasome into peptide aldehydes is presented. Such covalent and reversible inhibitors differ in their primary structures and chemical moieties attached to their N‐terminal amino group. Inhibitory potency is primarily tested against proteolytic subunits of human constitutive 20S proteasome (β1c, β2c, and β5c subunits), but in some cases, also against 20S immunoproteasome β5i. Most of the peptide aldehydes act nonspecifically and bind equipotently to the corresponding proteolytic subunits of both forms of proteasome (β5c and β5i). Two inhibitors are 2.7‐times more specific for immunoproteasome over its constitutive counterpart. The antitumor activity of the selected inhibitors and MG132 (used here as the reference) is analyzed using MTT assay against nonmalignant human fetal osteoblastic hFOB 1.19, malignant human osteosarcoma MG‐63, human pancreatic cancer MiaPaCa‐2, and human acute leukemia Jurkat T cell lines. All inhibitors tested are able to decrease cell viability in a concentration‐dependent manner. One of the peptide aldehydes exerted stronger, as compared to the MG132, activity against human glioblastoma cell line U87‐MG. Moreover, its combination with dinaciclib, which is a novel, potent inhibitor of cyclin‐dependent kinases, reduces cellular metabolic activity more potently as compared to either proteasome inhibitor or dinaciclib alone.

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Proteasome inhibitors in cancer therapy

Cited by 762 publications

References 142 publications

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis

The eIF2-alpha kinase HRI: a potential target beyond the red blood cell

Inhibition of human constitutive 20S proteasome and 20S immunoproteasome with novel N‐terminally modified peptide aldehydes and their antitumor activity

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