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

Yu, Guangyang; Wang, Xuan; Zheng, Su-Su; Gao, Xiaomei; Jia, Qingan; Zhu, Wen‐Wei; Lu, Lu; Jia, Hongyan; Chen, Jinhong; Dong, Qiongzhu; Lü, Ming; Qin, Lun–Xiu

doi:10.1159/000490210

Cited by 27 publications

(38 citation statements)

References 41 publications

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“…Inhibition of IκBα degradation by proteasome inhibitors prevents the release and nuclear entry of NF-κB. RA190 was previously reported to block NF-κB signaling via stabilization of p-IκBα [11,12]. Here, we show that RA190 inhibits the NF-κB pathway by preventing IκBα degradation by the proteasome and causing the cytoplasmic accumulation of NF-κB.…”

Section: Introductionsupporting

confidence: 47%

“…The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of RPN13 (ADRM1), a key ubiquitin receptor in the 19S regulatory particle of the proteasome, and inhibits its function causing rapid accumulation of polyubiquitinated proteins. RA190 showed a therapeutic effect in multiple myeloma, cholangiocarconoma [11], ovarian and cervical cancer models in previous studies [12]. In this study, we examine the impact of RA190 on HCC, including the levels of polyubiquitinated proteins, Endoplasmic Reticulum Stress, apoptosis and its therapeutic potential.…”

Section: Introductionmentioning

confidence: 91%

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Bis-benzylidine Piperidone RA190 Treatment of Hepatocellular Carcinoma via Binding RPN13 and Inhibiting NF-κB Signaling

Soong

Ravi

Roden

et al. 2020

Preprint

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Background Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer mortality worldwide. The development of new anticancer agents targeting different pathways is imperative to improve the advanced HCC. The aberrant metabolism and aggressive growth of cancer cells can render them particularly susceptible to proteasome inhibition, as first demonstrated by the success of bortezomib treatment for 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, a ubiquitin receptor subunit of the proteasome’s 19S regulatory particle. RA190 treatment inhibits proteasome function, causing rapid accumulation of polyubiquitinated proteins. Methods Human HCC cell lines were treated by RA190 in vitro in different concentration and time frame. We checked the killing effect and the possible mechanisms that lead the tumor apoptosis. We also performed the orthotopic HCC animal model to show the RA190 had significant killing effect in vivo . Results We showed RA190 is also toxic to HCC cells by triggering the rapid build-up of polyubiquitinated proteins, resulting in endoplasmic reticulum stress and the induction of cell death via apoptosis. Considerable evidence suggests that nuclear factor κB (NF-κB) signal is essential for promoting inflammation-associated cancer. Here, we showed that RA190 inhibited the NF-κB pathway in HCC by preventing the degradation of IκBα via the proteasome. Treatment of mice bearing an orthotopic HCC model with RA190 significantly reduced tumor growth. We therefore explored combining RA190 with a tyrosine kinase inhibitor currently used to the treat HCC, Sorafenib. Conclusions RA190 and Sorafenib exhibited synergetic killing of HCC cells in vitro , suggesting further exploration of such a combination treatment of HCC is warranted.

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Section: Introductionsupporting

confidence: 47%

Section: Introductionmentioning

confidence: 91%

Bis-benzylidine Piperidone RA190 Treatment of Hepatocellular Carcinoma via Binding RPN13 and Inhibiting NF-κB Signaling

Soong

Ravi

Roden

et al. 2020

Preprint

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“…The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of RPN13 (also called ADRM1), a key ubiquitin receptor in the 19S regulatory particle of the proteasome, and inhibits its function causing rapid accumulation of polyubiquitinated proteins. RA190 showed a therapeutic effect in multiple myeloma, cholangiocarcinoma [11], ovarian and cervical cancer models in previous studies [12]. In this study, we examine the impact of RA190 on HCC cells, including the levels of polyubiquitinated proteins, Endoplasmic Reticulum (ER) stress, apoptosis, and its therapeutic 5 potential against an orthotopic xenograft model.…”

Section: Introductionmentioning

confidence: 95%

Bis-benzylidine Piperidone RA190 Treatment of Hepatocellular Carcinoma via Binding RPN13 and Inhibiting NF-κB Signaling

Soong

Anchoori

Roden

et al. 2020

Preprint

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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.

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“…Although binding to UCH37 can also occur in vitro [6], several lines of evidence including cell labeling [10], degrader [11] and knockout studies [12] suggest that RPN13 is RA190's principle cellular target. RA190 and the related RA183 [13] exhibit antineoplastic activity, including against bortezomib-resistant MM, and against solid tumors in pre-clinical models of ovarian cancer [10,13,14], human papillomavirus (HPV)-associated and several other solid cancers [6,12,[15][16][17][18]. Like RA190 and RA183 [13], the diphenyldihaloketones CLEFMA and EF-24 also adduct to RPN13 and inhibit proteasome function [19], and herein we seek to further understand the pharmacophore.…”

Section: Introductionmentioning

confidence: 99%

Structure-function analyses of candidate small molecule RPN13 inhibitors with antitumor properties

et al. 2020

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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.

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

Cited by 27 publications

References 41 publications

Bis-benzylidine Piperidone RA190 Treatment of Hepatocellular Carcinoma via Binding RPN13 and Inhibiting NF-κB Signaling

Bis-benzylidine Piperidone RA190 Treatment of Hepatocellular Carcinoma via Binding RPN13 and Inhibiting NF-κB Signaling

Bis-benzylidine Piperidone RA190 Treatment of Hepatocellular Carcinoma via Binding RPN13 and Inhibiting NF-κB Signaling

Structure-function analyses of candidate small molecule RPN13 inhibitors with antitumor properties

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