LIVIVO - Search results -

Search results

Result 1 - 10 of total 14

Search options

Article ; Online: Development and anticancer properties of Up284, a spirocyclic candidate ADRM1/RPN13 inhibitor.

Anchoori, Ravi K / Anchoori, Vidyasagar / Lam, Brandon / Tseng, Ssu-Hsueh / Das, Samarjit / Velasquez, Fernanda Carrizo / Karanam, Balasubramanyam / Poddatoori, Deepika / Patnam, Ramesh / Rudek, Michelle A / Chang, Yung-Nien / Roden, Richard B S

PloS one

2023 Volume 18, Issue 6, Page(s) e0285221

Abstract: Bortezomib has been successful for treatment of multiple myeloma, but not against solid tumors, and toxicities of neuropathy, thrombocytopenia and the emergence of resistance have triggered efforts to find alternative proteasome inhibitors. Bis- ... ...

Abstract	Bortezomib has been successful for treatment of multiple myeloma, but not against solid tumors, and toxicities of neuropathy, thrombocytopenia and the emergence of resistance have triggered efforts to find alternative proteasome inhibitors. Bis-benzylidine piperidones such as RA190 covalently bind ADRM1/RPN13, a ubiquitin receptor that supports recognition of polyubiquitinated substrates of the proteasome and their subsequent deububiqutination and degradation. While these candidate RPN13 inhibitors (iRPN13) show promising anticancer activity in mouse models of cancer, they have suboptimal drug-like properties. Here we describe Up284, a novel candidate iRPN13 possessing a central spiro-carbon ring in place of RA190's problematic piperidone core. Cell lines derived from diverse cancer types (ovarian, triple negative breast, colon, cervical and prostate cancers, multiple myeloma and glioblastoma) were sensitive to Up284, including several lines resistant to bortezomib or cisplatin. Up284 and cisplatin showed synergistic cytotoxicity in vitro. Up284-induced cytotoxicity was associated with mitochondrial dysfunction, elevated levels of reactive oxygen species, accumulation of very high molecular weight polyubiquitinated protein aggregates, an unfolded protein response and the early onset of apoptosis. Up284 and RA190, but not bortezomib, enhanced antigen presentation in vitro. Up284 cleared from plasma in a few hours and accumulated in major organs by 24 h. A single dose of Up284, when administered to mice intra peritoneally or orally, inhibited proteasome function in both muscle and tumor for >48 h. Up284 was well tolerated by mice in repeat dose studies. Up284 demonstrated therapeutic activity in xenograft, syngeneic and genetically-engineered murine models of ovarian cancer.
MeSH term(s)	Humans ; Male ; Female ; Animals ; Mice ; Multiple Myeloma ; Cisplatin ; Proteasome Endopeptidase Complex ; Ovarian Neoplasms ; Bortezomib/pharmacology ; Intracellular Signaling Peptides and Proteins
Chemical Substances	Cisplatin (Q20Q21Q62J) ; RA190 ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Bortezomib (69G8BD63PP) ; ADRM1 protein, human ; Intracellular Signaling Peptides and Proteins
Language	English
Publishing date	2023-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0285221
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Article ; Online: The Proteasome Ubiquitin Receptor hRpn13 and Its Interacting Deubiquitinating Enzyme Uch37 Are Required for Proper Cell Cycle Progression.

Randles, Leah / Anchoori, Ravi K / Roden, Richard B S / Walters, Kylie J

The Journal of biological chemistry

2016 Volume 291, Issue 16, Page(s) 8773–8783

Abstract: Recently, we reported that bisbenzylidine piperidone RA190 adducts to Cys-88 of the proteasome ubiquitin receptor hRpn13, triggering accumulation of ubiquitinated proteins and endoplasmic reticulum stress-related apoptosis in various cancer cell lines. ... ...

Abstract	Recently, we reported that bisbenzylidine piperidone RA190 adducts to Cys-88 of the proteasome ubiquitin receptor hRpn13, triggering accumulation of ubiquitinated proteins and endoplasmic reticulum stress-related apoptosis in various cancer cell lines. hRpn13 contains an N-terminal pleckstrin-like receptor for ubiquitin domain that binds ubiquitin and docks it into the proteasome as well as a C-terminal deubiquitinase adaptor (DEUBAD) domain that binds the deubiquitinating enzyme Uch37. Here we report that hRpn13 and Uch37 are required for proper cell cycle progression and that their protein knockdown leads to stalling at G0/G1 Moreover, serum-starved cells display reduced hRpn13 and Uch37 protein levels with hallmarks of G0/G1 stalling and recovery to their steady-state protein levels following release from nutrient deprivation. Interestingly, loss of hRpn13 correlates with a small but statistically significant reduction in Uch37 protein levels, suggesting that hRpn13 interaction may stabilize this deubiquitinating enzyme in human cells. We also find that RA190 treatment leads to a loss of S phase, suggesting a block of DNA replication, and G2 arrest by using fluorescence-activated cell sorting. Uch37 deprivation further indicated a reduction of DNA replication and G0/G1 stalling. Overall, this work implicates hRpn13 and Uch37 in cell cycle progression, providing a rationale for their function in cellular proliferation and for the apoptotic effect of the hRpn13-targeting molecule RA190.
MeSH term(s)	Cell Cycle/drug effects ; Cell Cycle/physiology ; DNA Replication/drug effects ; DNA Replication/physiology ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Ubiquitin Thiolesterase/genetics ; Ubiquitin Thiolesterase/metabolism
Chemical Substances	ADRM1 protein, human ; Intracellular Signaling Peptides and Proteins ; Membrane Glycoproteins ; UCHL5 protein, human (EC 3.4.19.12) ; Ubiquitin Thiolesterase (EC 3.4.19.12)
Language	English
Publishing date	2016-02-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M115.694588
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Uc I Zs.108: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Structure-function analyses of candidate small molecule RPN13 inhibitors with antitumor properties.

Anchoori, Ravi K / Tan, Marietta / Tseng, Ssu-Hsueh / Peng, Shiwen / Soong, Ruey-Shyang / Algethami, Aliyah / Foran, Palmer / Das, Samarjit / Wang, Chenguang / Wang, Tian-Li / Liang, Hong / Hung, Chien-Fu / Roden, Richard B S

PloS one

2020 Volume 15, Issue 1, Page(s) e0227727

Abstract: We sought to design ubiquitin-proteasome system inhibitors active against solid cancers by targeting ubiquitin receptor RPN13 within the proteasome's 19S regulatory particle. The prototypic bis-benzylidine piperidone-based inhibitor RA190 is a michael ... ...

Abstract	We sought to design ubiquitin-proteasome system inhibitors active against solid cancers by targeting ubiquitin receptor RPN13 within the proteasome's 19S regulatory particle. The prototypic bis-benzylidine piperidone-based inhibitor RA190 is a michael acceptor that adducts Cysteine 88 of RPN13. In probing the pharmacophore, we showed the benefit of the central nitrogen-bearing piperidone ring moiety compared to a cyclohexanone, the importance of the span of the aromatic wings from the central enone-piperidone ring, the contribution of both wings, and that substituents with stronger electron withdrawing groups were more cytotoxic. Potency was further enhanced by coupling of a second warhead to the central nitrogen-bearing piperidone as RA375 exhibited ten-fold greater activity against cancer lines than RA190, reflecting its nitro ring substituents and the addition of a chloroacetamide warhead. Treatment with RA375 caused a rapid and profound accumulation of high molecular weight polyubiquitinated proteins and reduced intracellular glutathione levels, which produce endoplasmic reticulum and oxidative stress, and trigger apoptosis. RA375 was highly active against cell lines of multiple myeloma and diverse solid cancers, and demonstrated a wide therapeutic window against normal cells. For cervical and head and neck cancer cell lines, those associated with human papillomavirus were significantly more sensitive to RA375. While ARID1A-deficiency also enhanced sensitivity 4-fold, RA375 was active against all ovarian cancer cell lines tested. RA375 inhibited proteasome function in muscle for >72h after single i.p. administration to mice, and treatment reduced tumor burden and extended survival in mice carrying an orthotopic human xenograft derived from a clear cell ovarian carcinoma.
MeSH term(s)	Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Benzylidene Compounds/chemistry ; Benzylidene Compounds/pharmacology ; Benzylidene Compounds/therapeutic use ; Cell Line, Tumor ; Female ; Humans ; Inhibitory Concentration 50 ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins/genetics ; Mice ; Molecular Structure ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors/chemistry ; Proteasome Inhibitors/pharmacology ; Proteasome Inhibitors/therapeutic use ; Protein Binding ; Structure-Activity Relationship ; Ubiquitin/antagonists & inhibitors ; Ubiquitin/metabolism ; Ubiquitinated Proteins/metabolism ; Ubiquitination/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	ADRM1 protein, human ; Antineoplastic Agents ; Benzylidene Compounds ; Intracellular Signaling Peptides and Proteins ; Proteasome Inhibitors ; RA190 ; Ubiquitin ; Ubiquitinated Proteins ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2020-01-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0227727
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Bis-benzylidine Piperidone RA190 treatment of hepatocellular carcinoma via binding RPN13 and inhibiting NF-κB signaling.

Soong, Ruey-Shyang / Anchoori, Ravi K / Roden, Richard B S / Cho, Rou-Ling / Chen, Yi-Chan / Tseng, Sheng-Chieh / Huang, Yun-Li / Liao, Po-Cheng / Shyu, Yu-Chiau

BMC cancer

2020 Volume 20, Issue 1, Page(s) 386

Abstract: Background: According to GLOBOSCAN, hepatocellular carcinoma (HCC) claimed 782,000 lives in 2018. The tyrosine kinase inhibitor sofafenib is used to treat HCC, but new anticancer agents targeting different pathways are urgently needed to improve ... ...

Abstract	Background: According to GLOBOSCAN, hepatocellular carcinoma (HCC) claimed 782,000 lives in 2018. The tyrosine kinase inhibitor sofafenib is used to treat HCC, but new anticancer agents targeting different pathways are urgently needed to improve outcomes for patients with advanced disease. The aberrant metabolism and aggressive growth of cancer cells can render them particularly susceptible to proteasome inhibition, as demonstrated by bortezomib treatment of multiple myeloma. However, resistance does emerge, and this 20S proteasome inhibitor has not proven active against HCC. The bis-benzylidine piperidone RA190 represents a novel class of proteasome inhibitor that covalently binds to cysteine 88 of RPN13, an ubiquitin receptor subunit of the proteasome's 19S regulatory particle. RA190 treatment inhibits proteasome function, causing rapid accumulation of polyubiquitinated proteins. Considerable evidence suggests that nuclear factor κB (NF-κB) signaling, which is dependent upon the proteasome, is a major driver of inflammation-associated cancers, including HCC. Methods: Human HCC cell lines were treated with titrations of RA190. The time course of endoplasmic reticulum stress and NF-κB-related mechanisms by which RA190 may trigger apoptosis were assessed. The therapeutic activity of RA190 was also determined in an orthotopic HCC xenograft mouse model. Results: RA190 is toxic to HCC cells and synergizes with sofafenib. RA190 triggers rapid accumulation of polyubiquitinated proteins, unresolved endoplasmic reticulum stress, and cell death via apoptosis. RA190 blocks proteasomal degradation of IκBα and consequent release of NF-κB into the nuclei of HCC cells. Treatment of mice bearing an orthotopic HCC model with RA190 significantly reduced tumor growth. Conclusions: RA190 has therapeutic activity in a xenograft model, and with sorafenib exhibited synergetic killing of HCC cells in vitro, suggesting further exploration of such a combination treatment of HCC is warranted.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Apoptosis ; Benzylidene Compounds/pharmacology ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Cell Proliferation ; Endoplasmic Reticulum Stress/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; NF-kappa B/antagonists & inhibitors ; Tumor Cells, Cultured ; Ubiquitin/metabolism ; Ubiquitination ; Xenograft Model Antitumor Assays
Chemical Substances	ADRM1 protein, human ; Antineoplastic Agents ; Benzylidene Compounds ; Intracellular Signaling Peptides and Proteins ; NF-kappa B ; RA190 ; Ubiquitin
Language	English
Publishing date	2020-05-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2041352-X
ISSN	1471-2407 ; 1471-2407
ISSN (online)	1471-2407
ISSN	1471-2407
DOI	10.1186/s12885-020-06896-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors.

Anchoori, Ravi K / George, Logan / Tseng, Ssu-Hsueh / Lam, Brandon / Polkampally, Srinidhi / Amiano, Anjali D / Foran, Palmer / Tsingine, Hannah / Samanapally, Harideep / Carrizo Velasquez, Fernanda / Das, Samarjit / Xing, Deyin / Bin Salam, Ahmad / Karanam, Balasubramanyam / Hung, Chien-Fu / Roden, Richard B S

PloS one

2021 Volume 16, Issue 9, Page(s) e0256937

Abstract: Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non- ... ...

Abstract	Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome's 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Here we demonstrate that rendering these candidate RPN13 inhibitors chiral and asymmetric through the addition of a single methyl to the core piperidone moiety increases their potency against cancer cell lines, with the S-isomer being more active than the R-isomer. The enhanced cancer cell cytotoxicities of these compounds are associated with improved binding to RPN13 in cell lysates, ATP depletion by inhibition of glycolysis and mitochondrial electron chain transport, mitochondrial depolarization and perinuclear clustering, oxidative stress and glutathione depletion, and rapid accumulation of high molecular weight polyubiquitinated proteins with a consequent unresolved ubiquitin proteasome system (UPS) stress response. Cytotoxicity was associated with an early biomarker of apoptosis, increased surface annexin V binding. As for cisplatin, BRCA2 and ATM deficiency conferred increased sensitivity to these iRPN13s. Ubiquitination plays an important role in coordinating DNA damage repair and the iRPN13s may compromise this process by depletion of monomeric ubiquitin following its sequestration in high molecular weight polyubiquitinated protein aggregates. Indeed, a synergistic cytotoxic response was evident upon treatment of several ovarian cancer cell lines with either cisplatin or doxorubicin and our new candidate iRPN13s, suggesting that such a combination approach warrants further exploration for the treatment of ovarian cancer.
MeSH term(s)	Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Benzylidene Compounds/chemistry ; Benzylidene Compounds/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Female ; Humans ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Ovarian Neoplasms/drug therapy ; Ubiquitination/drug effects
Chemical Substances	ADRM1 protein, human ; Antineoplastic Agents ; Benzylidene Compounds ; Intracellular Signaling Peptides and Proteins ; RA190
Language	English
Publishing date	2021-09-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0256937
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: mTORC1 feedback to AKT modulates lysosomal biogenesis through MiT/TFE regulation.

Asrani, Kaushal / Murali, Sanjana / Lam, Brandon / Na, Chan-Hyun / Phatak, Pornima / Sood, Akshay / Kaur, Harsimar / Khan, Zoya / Noë, Michaël / Anchoori, Ravi K / Talbot, C Conover / Smith, Barbara / Skaro, Michael / Lotan, Tamara L

The Journal of clinical investigation

2019 Volume 129, Issue 12, Page(s) 5584–5599

Abstract: The microphthalmia family of transcription factors (MiT/TFEs) controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. However, the mechanisms by which cells with constitutive mTORC1 signaling maintain lysosomal catabolism ...

Abstract	The microphthalmia family of transcription factors (MiT/TFEs) controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. However, the mechanisms by which cells with constitutive mTORC1 signaling maintain lysosomal catabolism remain to be elucidated. Using the murine epidermis as a model system, we found that epidermal Tsc1 deletion resulted in a phenotype characterized by wavy hair and curly whiskers, and was associated with increased EGFR and HER2 degradation. Unexpectedly, constitutive mTORC1 activation with Tsc1 loss increased lysosomal content via upregulated expression and activity of MiT/TFEs, whereas genetic deletion of Rheb or Rptor or prolonged pharmacologic mTORC1 inactivation had the reverse effect. This paradoxical increase in lysosomal biogenesis by mTORC1 was mediated by feedback inhibition of AKT, and a resulting suppression of AKT-induced MiT/TFE downregulation. Thus, inhibiting hyperactive AKT signaling in the context of mTORC1 loss-of-function fully restored MiT/TFE expression and activity. These data suggest that signaling feedback loops work to restrain or maintain cellular lysosomal content during chronically inhibited or constitutively active mTORC1 signaling, respectively, and reveal a mechanism by which mTORC1 regulates upstream receptor tyrosine kinase signaling.
MeSH term(s)	Active Transport, Cell Nucleus ; Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Cells, Cultured ; ErbB Receptors/physiology ; Lysosomes/physiology ; Mechanistic Target of Rapamycin Complex 1/physiology ; Mice ; Microphthalmia-Associated Transcription Factor/physiology ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-akt/physiology ; Receptor, ErbB-2/physiology ; Tuberous Sclerosis Complex 1 Protein/physiology
Chemical Substances	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Microphthalmia-Associated Transcription Factor ; Tcfeb protein, mouse ; Tsc1 protein, mouse ; Tuberous Sclerosis Complex 1 Protein ; ErbB Receptors (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2019-09-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI128287
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Ua VI Zs.184: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article: Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer.

Anchoori, Ravi K / Jiang, Rosie / Peng, Shiwen / Soong, Ruey-Shyang / Algethami, Aliyah / Rudek, Michelle A / Anders, Nicole / Hung, Chien-Fu / Chen, Xiang / Lu, Xiuxiu / Kayode, Olumide / Dyba, Marzena / Walters, Kylie J / Roden, Richard B S

ACS omega

2018 Volume 3, Issue 9, Page(s) 11917–11929

Abstract: Substitution of ... ...

Abstract	Substitution of the
Language	English
Publishing date	2018-09-27
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN	2470-1343
DOI	10.1021/acsomega.8b01479
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article ; Online: Early and consistent overexpression of ADRM1 in ovarian high-grade serous carcinoma.

Jiang, Rosie T / Yemelyanova, Anna / Xing, Deyin / Anchoori, Ravi K / Hamazaki, Jun / Murata, Shigeo / Seidman, Jeffrey D / Wang, Tian-Li / Roden, Richard B S

Journal of ovarian research

2017 Volume 10, Issue 1, Page(s) 53

Abstract: Background: Ovarian carcinoma is highly dependent on the ubiquitin proteasome system (UPS), but its clinical response to treatment with the proteasome inhibitor bortezomib has been disappointing. This has driven exploration of alternate approaches to ... ...

Abstract	Background: Ovarian carcinoma is highly dependent on the ubiquitin proteasome system (UPS), but its clinical response to treatment with the proteasome inhibitor bortezomib has been disappointing. This has driven exploration of alternate approaches to target the UPS in ovarian cancer. Recently, proteasome inhibitors targeting the 19S regulatory particle-associated RPN13 protein have been described, such as RA190. RPN13, which is encoded by ADRM1, facilitates the recognition by the proteasome of its polyubiquinated substrates. Inhibition of RPN13 produces a rapid, toxic accumulation of polyubiquitinated proteins in ovarian and other cancer cells, triggering apoptosis. Here, we sought to determine if RPN13 is available as a target in precursors of ovarian/fallopian tube cancer as well as all advanced cases, and the impact of increased ADRM1 gene copy number on sensitivity of ovarian cancer to RA190. Methods: ADRM1 mRNA was quantified by RNAscope in situ hybridization and RPN13 protein detected by immunohistochemistry in high grade serous carcinoma (HGSC) of the ovary and serous tubal intraepithelial carcinoma (STIC). Amplification of ADRM1 and sensitivity to RA190 were determined in ovarian cancer cell lines. Results: Here, we demonstrate that expression of ADRM1mRNA is significantly elevated in STIC and HGSC as compared to normal fallopian tube epithelium. ADRM1 mRNA and RPN13 were ubiquitously and robustly expressed in ovarian carcinoma tissue and cell lines. No correlation was found between ADRM1 amplification and sensitivity of ovarian cancer cell lines to RA190, but all were susceptible. Conclusions: RPN13 can potentially be targeted by RA190 in both in situ and metastatic ovarian carcinoma. Ovarian cancer cell lines are sensitive to RA190 regardless of whether the ADRM1 gene is amplified.
Language	English
Publishing date	2017-08-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2455679-8
ISSN	1757-2215 ; 1757-2215
ISSN (online)	1757-2215
ISSN	1757-2215
DOI	10.1186/s13048-017-0347-y
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: RPN13/ADRM1 inhibitor reverses immunosuppression by myeloid-derived suppressor cells.

Soong, Ruey-Shyang / Anchoori, Ravi K / Yang, Benjamin / Yang, Andrew / Tseng, Ssu-Hsueh / He, Liangmei / Tsai, Ya-Chea / Roden, Richard B S / Hung, Chien-Fu

Oncotarget

2016 Volume 7, Issue 42, Page(s) 68489–68502

Abstract: Myeloid-derived-suppressor cells (MDSCs) are key mediators of immune suppression in the ovarian tumor microenvironment. Modulation of MDSC function to relieve immunosuppression may enhance the immunologic clearance of tumors. The bis-benzylidine ... ...

Abstract	Myeloid-derived-suppressor cells (MDSCs) are key mediators of immune suppression in the ovarian tumor microenvironment. Modulation of MDSC function to relieve immunosuppression may enhance the immunologic clearance of tumors. The bis-benzylidine piperidone RA190 binds to the ubiquitin receptor RPN13/ADRM1 on the 19S regulatory particle of the proteasome and directly kills ovarian cancer cells by triggering proteotoxic stress. Here we examine the effect of RA190 treatment on the immunosuppression induced by MDSCs in the tumor microenvironment, specifically on the immunosuppression induced by MDSCs. We show that RA190 reduces the expression of Stat3 and the levels of key immunosuppressive enzymes and cytokines arginase, iNOS, and IL-10 in MDSCs, while boosting expression of the immunostimulatory cytokine IL-12. Furthermore, we show that the RA190-treated MDSCs lost their capacity to suppress CD8+ T cell function. Finally, we show that RA190 treatment of mice bearing syngeneic ovarian tumor elicits potent CD8+ T cell antitumor immune responses and improves tumor control and survival. These data suggest the potential of RA190 for ovarian cancer treatment by both direct killing of tumor cells via proteasome inhibition and relief of MDSC-mediated suppression of CD8 T cell-dependent antitumor immunity elicited by the apoptotic tumor cells.
MeSH term(s)	Animals ; Benzylidene Compounds/metabolism ; Benzylidene Compounds/pharmacology ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cell Adhesion Molecules/antagonists & inhibitors ; Cell Adhesion Molecules/immunology ; Cell Adhesion Molecules/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; Cells, Cultured ; Female ; HEK293 Cells ; Humans ; Immune Tolerance/drug effects ; Immune Tolerance/immunology ; Intracellular Signaling Peptides and Proteins ; Kaplan-Meier Estimate ; Mice, Inbred C57BL ; Myeloid-Derived Suppressor Cells/drug effects ; Myeloid-Derived Suppressor Cells/immunology ; Myeloid-Derived Suppressor Cells/metabolism ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/immunology ; Ovarian Neoplasms/metabolism ; RNA Interference ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/immunology
Chemical Substances	Adrm1 protein, mouse ; Benzylidene Compounds ; Cell Adhesion Molecules ; Intracellular Signaling Peptides and Proteins ; RA190 ; STAT3 Transcription Factor
Language	English
Publishing date	2016-10-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.12095
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: A bis-benzylidine piperidone targeting proteasome ubiquitin receptor RPN13/ADRM1 as a therapy for cancer.

Anchoori, Ravi K / Karanam, Balasubramanyam / Peng, Shiwen / Wang, Joshua W / Jiang, Rosie / Tanno, Toshihiko / Orlowski, Robert Z / Matsui, William / Zhao, Ming / Rudek, Michelle A / Hung, Chien-fu / Chen, Xiang / Walters, Kylie J / Roden, Richard B S

Cancer cell

2013 Volume 24, Issue 6, Page(s) 791–805

Abstract: The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of ubiquitin receptor RPN13 in the 19S regulatory particle and inhibits proteasome function, triggering rapid accumulation of polyubiquitinated proteins. Multiple myeloma (MM) lines, ... ...

Abstract	The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of ubiquitin receptor RPN13 in the 19S regulatory particle and inhibits proteasome function, triggering rapid accumulation of polyubiquitinated proteins. Multiple myeloma (MM) lines, even those resistant to bortezomib, were sensitive to RA190 via endoplasmic reticulum stress-related apoptosis. RA190 stabilized targets of human papillomavirus (HPV) E6 oncoprotein, and preferentially killed HPV-transformed cells. After oral or intraperitoneal dosing of mice, RA190 distributed to plasma and major organs except the brain and inhibited proteasome function in skin and muscle. RA190 administration profoundly reduced growth of MM and ovarian cancer xenografts, and oral RA190 treatment retarded HPV16(+) syngeneic mouse tumor growth, without affecting spontaneous HPV-specific CD8(+) T cell responses, suggesting its therapeutic potential.
MeSH term(s)	Animals ; Boronic Acids/pharmacology ; Bortezomib ; Cell Line, Tumor ; Endoplasmic Reticulum Stress ; Female ; Genes, p53 ; Humans ; Intracellular Signaling Peptides and Proteins ; Membrane Glycoproteins/antagonists & inhibitors ; Membrane Glycoproteins/chemistry ; Membrane Glycoproteins/physiology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplasms/drug therapy ; Neoplasms/pathology ; Piperidones/pharmacology ; Proteasome Inhibitors/pharmacokinetics ; Proteasome Inhibitors/pharmacology ; Pyrazines/pharmacology ; Ubiquitination
Chemical Substances	ADRM1 protein, human ; Boronic Acids ; Intracellular Signaling Peptides and Proteins ; Membrane Glycoproteins ; Piperidones ; Proteasome Inhibitors ; Pyrazines ; Bortezomib (69G8BD63PP)
Language	English
Publishing date	2013-12-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccr.2013.11.001
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 5650: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 104: Show issues

Order via subito

Details ▾

To top

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

Order via subito

More links

Kategorien

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito