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      YPC‐21661 and YPC‐22026, novel small molecules, inhibit ZNF143 activity in vitro and in vivo

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          Abstract

          Zinc‐finger protein 143 (ZNF143) is a transcription factor that is involved in anticancer drug resistance and cancer cell survival. In the present study, we identified a novel small molecule N‐(5‐bromo‐2‐methoxyphenyl)‐3‐(pyridine‐3‐yl) propiolamide (YPC‐21661) that inhibited ZNF143 promoter activity and down‐regulated the expression of the ZNF143‐regulated genes, RAD51, PLK1, and Survivin, by inhibiting the binding of ZNF143 to DNA. In addition, YPC‐21661 was cytotoxic and induced apoptosis in the human colon cancer cell line, HCT116 and human prostate cancer cell line, PC‐3. 2‐(pyridine‐3‐ylethynyl)‐5‐(2‐(trifluoromethoxy)phenyl)‐1,3,4‐oxadiazole (YPC‐22026), a metabolically stable derivative of YPC‐21661, induced tumor regression accompanied by the suppression of ZNF143‐regulated genes in a mouse xenograft model. The present study revealed that the inhibition of ZNF143 activity by small molecules induced tumor regression in vitro and in vivo; therefore, ZNF143 is a promising target of cancer therapeutics.

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          Small-molecule c-Myc inhibitor, 10058-F4, inhibits proliferation, downregulates human telomerase reverse transcriptase and enhances chemosensitivity in human hepatocellular carcinoma cells.

          Che-Pin Lin, Jean-Dean Liu, Jyh-Ming Chow … (2007)
          c-Myc oncogene is critical for the development of hepatocellular carcinoma. Given the successful use of small-molecule inhibitors on cancers, targeting c-Myc with small-molecule inhibitors represents a promising approach. The potential of using small-molecule c-Myc inhibitor, 10058-F4, was evaluated on hepatocellular carcinoma cell lines, HepG2 and Hep3B cells. HepG2 cells were more sensitive to 10058-F4 than Hep3B cells, as demonstrated by reduced cell viability, marked morphological changes and decreased c-Myc levels. 10058-F4 arrested the cell cycle (at G0/G1 phase) and induced apoptosis upon extended treatment. These observations might be attributable to the increased cyclin-dependent kinase inhibitor, p21, and decreased cyclin D3 levels. Besides, 10058-F4 also significantly decreased the alpha-fetoprotein levels, an indicator for hepatocellular carcinoma differentiation. We further found that 10058-F4 inhibited the transactivation of human telomerase reverse transcriptase, downregulated human telomerase reverse transcriptase expression and abrogated telomerase activity. In addition, pretreatment with 10058-F4 increased the chemosensitivity of HepG2 cells to low-dose doxorubicin, 5-fluorouracil and cisplatin. Therefore, small-molecule c-Myc inhibitors might represent a novel agent, alone or in combination with conventional chemotherapeutic agents, for anti-hepatocellular carcinoma therapy.
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            Transcription of the human cell cycle regulated BUB1B gene requires hStaf/ZNF143

            Evelyne Myslinski, Marie-Aline Gerard, Alain Krol … (2007)
            BubR1 is a key protein mediating spindle checkpoint activation. Loss of this checkpoint control results in chromosomal instability and aneuploidy. The transcriptional regulation of the cell cycle regulated human BUB1B gene, which encodes BubR1, was investigated in this report. A minimal BUB1B gene promoter containing 464 bp upstream from the translation initiation codon was sufficient for cell cycle regulated promoter activity. A pivotal role for transcription factor hStaf/ZNF143 in the expression of the BUB1B gene was demonstrated through gel retardation assays, transient expression of mutant BUB1B promoter–reporter gene constructs and chromatin immunoprecipitation assay. Two phylogenetically conserved hStaf/ZNF143-binding sites (SBS) were identified which are indispensable for BUB1B promoter activity. In addition, we found that the domain covering the transcription start sites contains conserved boxes homologous to initiator (Inr), cell cycle dependent (CDE) and cell cycle genes homology regions (CHR) elements. Mutations within the CDE and CHR elements led to diminished cell cycle regulation of BUB1B transcription. These results demonstrate that BUB1B gene transcription is positively regulated by hStaf/ZNF143, a ubiquitously expressed factor, and that the CDE-CHR tandem element was essential for G2/M-specific transcription of the BUB1B gene.
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              Triptolide abrogates growth of colon cancer and induces cell cycle arrest by inhibiting transcriptional activation of E2F.

              Veena Sangwan, Lihua Li, Rajinder Dawra … (2015)
              Despite significant progress in diagnostics and therapeutics, over 50 thousand patients die from colorectal cancer annually. Hence, there is urgent need for new lines of treatment. Triptolide, a natural compound isolated from the Chinese herb Tripterygium wilfordii, is effective against multiple cancers. We have synthesized a water soluble analog of triptolide, named Minnelide, which is currently in phase I trial against pancreatic cancer. The aims of the current study were to evaluate whether triptolide/Minnelide is effective against colorectal cancer and to elucidate the mechanism by which triptolide induces cell death in colorectal cancer. Efficacy of Minnelide was evaluated in subcutaneous xenograft and liver metastasis model of colorectal cancer. For mechanistic studies, colon cancer cell lines HCT116 and HT29 were treated with triptolide and the effect on viability, caspase activation, annexin positivity, lactate dehydrogenase release, and cell cycle progression was evaluated. Effect of triptolide on E2F transcriptional activity, mRNA levels of E2F-dependent genes, E2F1- retinoblastoma protein (Rb) binding, and proteins levels of regulator of G1-S transition was also measured. DNA binding of E2F1 was evaluated by chromatin immunoprecipitation assay. Triptolide decreased colon cancer cell viability in a dose- and time-dependent fashion. Minnelide markedly inhibited the growth of colon cancer in the xenograft and liver metastasis model of colon cancer and more than doubles the median survival of animals with liver metastases from colon cancer. Mechanistically, we demonstrate that at low concentrations triptolide induces apoptotic cell death but at higher concentrations it induces cell cycle arrest. Our data suggest that triptolide is able to induce G1 cell cycle arrest by inhibiting transcriptional activation of E2F1. Our data also show that triptolide downregulates E2F activity by potentially modulating events downstream of DNA binding. Therefore, we conclude that Triptolide and Minnelide are effective against colon cancer in multiple pre-clinical models.
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                Author and article information

                Contributors
                Hirotaka Haibara:
                ORCID: http://orcid.org/0000-0001-5492-0134
                hirotaka-haibara@yakult.co.jp
                Journal
                Journal ID (nlm-ta): Cancer Sci
                Journal ID (iso-abbrev): Cancer Sci
                Journal ID (doi): 10.1111/(ISSN)1349-7006
                Journal ID (publisher-id): CAS
                Title: Cancer Science
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1347-9032
                ISSN (Electronic): 1349-7006
                Publication date (Electronic): 24 April 2017
                Publication date (Print): May 2017
                Volume: 108
                Issue: 5 ( doiID: 10.1111/cas.2017.108.issue-5 )
                Pages: 1042-1048
                Affiliations
                [ 1 ] Yakult Central InstituteYakult Honsha Co., Ltd. Kunitachi TokyoJapan
                [ 2 ]The University of Occupational and Environmental Health KitakyushuJapan
                Author notes
                [*] [* ] Correspondence

                Hirotaka Haibara, Yakult Central Institute, Yakult Honsha Co., Ltd., 5‐11 Izumi, Kunitachi‐shi, Tokyo, 186‐8650 Japan.

                Tel: +81‐42‐577‐8960; Fax: +81‐42‐577‐3020;

                E‐mail: hirotaka-haibara@ 123456yakult.co.jp

                Author information
                http://orcid.org/0000-0001-5492-0134
                Article
                Publisher ID: CAS13199
                DOI: 10.1111/cas.13199
                PMC ID: 5448606
                PubMed ID: 28192620
                SO-VID: e9c37ddf-fcf2-42b2-88e6-09d4822c5bd4
                Copyright © © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 03 October 2016
                Date revision received : 05 February 2017
                Date accepted : 07 February 2017
                Page count
                Figures: 7, Tables: 0, Pages: 7, Words: 4949
                Categories
                Subject: Original Article
                Subject: Original Articles
                Subject: Drug Discovery and Delivery
                Custom metadata
                source-schema-version-number 2.0
                component-id cas13199
                cover-date May 2017
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.9 mode:remove_FC converted:30.05.2017

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: anticancer drug,apoptosis,cell cycle,transcription factor,znf143
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: anticancer drug, apoptosis, cell cycle, transcription factor, znf143

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