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Targeting DNA Binding for NF-?B as an Anticancer Approach in Hepatocellular Carcinoma.

ABSTRACT: Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanistic targets. We identified potent compounds (1h, 2h, 5 and 8) exhibiting significant anticancer effects towards liver cancer cells (Hep3B) with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) relative values of cytotoxicity below 0.40, a value in the range of doxorubicin positive control with the value of 0.12. Bulky substituents and the presence of bromine atom, as well as the presence of sulfonamide linkage, are likely the favorable structural components for molecules exerting a strong anticancer effect. To the best of our knowledge, our findings obtained from chemical synthesis, in vitro cytotoxicity, bioinformatics-based molecular docking analysis (similarity ensemble approach, SEA),and electrophoretic mobility shift assay provided the first evidence in correlation to the anticancer activities of the selected compound 5 with the modulation on the binding of transcription factor NF-?B to its target DNA. Accordingly, compound 5 represented a lead structure for the development of quinoline-based NF-?B inhibitors and this work added novel information on the understanding of the mechanism of action for bioactive sulfonyl-containing quinoline compounds against hepatocellular carcinoma.

SUBMITTER: Chung PY

PROVIDER: S-EPMC6209864 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma.

Chung Po-Yee PY Lam Pik-Ling PL Zhou Yuan-Yuan YY Gasparello Jessica J Finotti Alessia A Chilin Adriana A Marzaro Giovanni G Gambari Roberto R Bian Zhao-Xiang ZX Kwok Wai-Ming WM Wong Wai-Yeung WY Wang Xi X Lam Alfred King-Yin AK Chan Albert Sun-Chi AS Li Xingshu X Ma Jessica Yuen-Wuen JY Chui Chung-Hin CH Lam Kim-Hung KH Tang Johnny Cheuk-On JC

Cells 20181022 10

Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanist ...[more]

PMID: 30360426

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Project description:BackgroundAccording 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.MethodsHuman 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.ResultsRA190 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.ConclusionsRA190 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.

Dataset Information

Targeting DNA Binding for NF-?B as an Anticancer Approach in Hepatocellular Carcinoma.

Publications

Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma.

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