Complexation of histone deacetylase inhibitor belinostat to Cu(II) prevents premature metabolic inactivation in vitro and demonstrates potent anti-cancer activity in vitro and ex vivo in colon cancer

  1. Finnegan, Ellen
  2. Ding, Wei
  3. Ude, Ziga
  4. Terer, Sara
  5. McGivern, Tadhg
  6. Blümel, Anna M.
  7. Kirwan, Grainne
  8. Shao, Xinxin
  9. Genua, Flavia
  10. Yin, Xiaofei
  11. Kel, Alexander
  12. Fattah, Sarinj
  13. Myer, Parvathi A.
  14. Cryan, Sally-Ann
  15. Prehn, Jochen H. M.
  16. O’Connor, Darran P.
  17. Brennan, Lorraine
  18. Yochum, Gregory
  19. Marmion, Celine J.
  20. Das, Sudipto

Download
13402_2023_Article_882.pdf 8,27MB
WeightNameValue
1000 Titel
  • Complexation of histone deacetylase inhibitor belinostat to Cu(II) prevents premature metabolic inactivation in vitro and demonstrates potent anti-cancer activity in vitro and ex vivo in colon cancer
1000 Autor/in
  1. Finnegan, Ellen |
  2. Ding, Wei |
  3. Ude, Ziga |
  4. Terer, Sara |
  5. McGivern, Tadhg |
  6. Blümel, Anna M. |
  7. Kirwan, Grainne |
  8. Shao, Xinxin |
  9. Genua, Flavia |
  10. Yin, Xiaofei |
  11. Kel, Alexander |
  12. Fattah, Sarinj |
  13. Myer, Parvathi A. |
  14. Cryan, Sally-Ann |
  15. Prehn, Jochen H. M. |
  16. O’Connor, Darran P. |
  17. Brennan, Lorraine |
  18. Yochum, Gregory |
  19. Marmion, Celine J. |
  20. Das, Sudipto |
1000 Verlag Springer Netherlands
1000 Erscheinungsjahr 2023
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2023-11-07
1000 Erschienen in
1000 Quellenangabe
  • 47(2):533-553
1000 Copyrightjahr
  • 2023
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1007/s13402-023-00882-x |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090832/ |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • <jats:title>Abstract</jats:title><jats:sec> <jats:title>Purpose</jats:title> <jats:p>The histone deacetylase inhibitor (HDACi), belinostat, has had limited therapeutic impact in solid tumors, such as colon cancer, due to its poor metabolic stability. Here we evaluated a novel belinostat prodrug, copper-bis-belinostat (Cubisbel), <jats:italic>in vitro</jats:italic> and <jats:italic>ex vivo</jats:italic>, designed to overcome the pharmacokinetic challenges of belinostat.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>The <jats:italic>in vitro</jats:italic> metabolism of each HDACi was evaluated in human liver microsomes (HLMs) using mass spectrometry. Next, the effect of belinostat and Cubisbel on cell growth, HDAC activity, apoptosis and cell cycle was assessed in three colon cancer cell lines. Gene expression alterations induced by both HDACis were determined using RNA-Seq, followed by <jats:italic>in silico</jats:italic> analysis to identify master regulators (MRs) of differentially expressed genes (DEGs). The effect of both HDACis on the viability of colon cancer patient-derived tumor organoids (PDTOs) was also examined.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Belinostat and Cubisbel significantly reduced colon cancer cell growth mediated through HDAC inhibition and apoptosis induction. Interestingly, the <jats:italic>in vitro</jats:italic> half-life of Cubisbel was significantly longer than belinostat. Belinostat and its Cu derivative commonly dysregulated numerous signalling and metabolic pathways while genes downregulated by Cubisbel were potentially controlled by <jats:italic>VEGFA, ERBB2</jats:italic> and <jats:italic>DUSP2</jats:italic> MRs. Treatment of colon cancer PDTOs with the HDACis resulted in a significant reduction in cell viability and downregulation of stem cell and proliferation markers.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Complexation of belinostat to Cu(II) does not alter the HDAC activity of belinostat, but instead significantly enhances its metabolic stability <jats:italic>in vitro</jats:italic> and targets anti-cancer pathways by perturbing key MRs in colon cancer. Complexation of HDACis to a metal ion might improve the efficacy of clinically used HDACis in patients with colon cancer.</jats:p> </jats:sec>
1000 Sacherschließung
lokal Cell Line, Tumor [MeSH]
lokal Epigenetic
lokal Organoids/drug effects [MeSH]
lokal Microsomes, Liver/drug effects [MeSH]
lokal Antineoplastic Agents/pharmacology [MeSH]
lokal Copper/chemistry [MeSH]
lokal Histone Deacetylase Inhibitor
lokal Copper Complex
lokal Hydroxamic Acids/pharmacology [MeSH]
lokal Organoids/metabolism [MeSH]
lokal Colonic Neoplasms/pathology [MeSH]
lokal Colonic Neoplasms/metabolism [MeSH]
lokal Microsomes, Liver/metabolism [MeSH]
lokal Histone Deacetylase Inhibitors/pharmacology [MeSH]
lokal Humans [MeSH]
lokal Apoptosis/drug effects [MeSH]
lokal Colonic Neoplasms/genetics [MeSH]
lokal Sulfonamides/pharmacology [MeSH]
lokal Organoids
lokal Colon Cancer
lokal Gene Expression Regulation, Neoplastic/drug effects [MeSH]
lokal Colonic Neoplasms/drug therapy [MeSH]
lokal Hydroxamic Acids/therapeutic use [MeSH]
lokal Research
lokal Antineoplastic Agents/therapeutic use [MeSH]
lokal Cell Proliferation/drug effects [MeSH]
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/uri/RmlubmVnYW4sIEVsbGVu|https://frl.publisso.de/adhoc/uri/RGluZywgV2Vp|https://frl.publisso.de/adhoc/uri/VWRlLCBaaWdh|https://frl.publisso.de/adhoc/uri/VGVyZXIsIFNhcmE=|https://frl.publisso.de/adhoc/uri/TWNHaXZlcm4sIFRhZGhn|https://frl.publisso.de/adhoc/uri/QmzDvG1lbCwgQW5uYSBNLg==|https://frl.publisso.de/adhoc/uri/S2lyd2FuLCBHcmFpbm5l|https://frl.publisso.de/adhoc/uri/U2hhbywgWGlueGlu|https://frl.publisso.de/adhoc/uri/R2VudWEsIEZsYXZpYQ==|https://frl.publisso.de/adhoc/uri/WWluLCBYaWFvZmVp|https://frl.publisso.de/adhoc/uri/S2VsLCBBbGV4YW5kZXI=|https://frl.publisso.de/adhoc/uri/RmF0dGFoLCBTYXJpbmo=|https://frl.publisso.de/adhoc/uri/TXllciwgUGFydmF0aGkgQS4=|https://frl.publisso.de/adhoc/uri/Q3J5YW4sIFNhbGx5LUFubg==|https://frl.publisso.de/adhoc/uri/UHJlaG4sIEpvY2hlbiBILiBNLg==|https://frl.publisso.de/adhoc/uri/T_KAmUNvbm5vciwgRGFycmFuIFAu|https://frl.publisso.de/adhoc/uri/QnJlbm5hbiwgTG9ycmFpbmU=|https://frl.publisso.de/adhoc/uri/WW9jaHVtLCBHcmVnb3J5|https://frl.publisso.de/adhoc/uri/TWFybWlvbiwgQ2VsaW5lIEou|https://frl.publisso.de/adhoc/uri/RGFzLCBTdWRpcHRv
1000 Hinweis
  • DeepGreen-ID: 25a2fc891c4a4b12a3d9d2764ad2a673 ; metadata provieded by: DeepGreen (https://www.oa-deepgreen.de/api/v1/), LIVIVO search scope life sciences (http://z3950.zbmed.de:6210/livivo), Crossref Unified Resource API (https://api.crossref.org/swagger-ui/index.html), to.science.api (https://frl.publisso.de/), ZDB JSON-API (beta) (https://zeitschriftendatenbank.de/api/), lobid - Dateninfrastruktur für Bibliotheken (https://lobid.org/resources/search)
1000 Label
1000 Förderer
  1. Irish Research Council |
  2. Science Foundation Ireland |
1000 Fördernummer
  1. -
  2. -
1000 Förderprogramm
  1. -
  2. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Irish Research Council |
    1000 Förderprogramm -
    1000 Fördernummer -
  2. 1000 joinedFunding-child
    1000 Förderer Science Foundation Ireland |
    1000 Förderprogramm -
    1000 Fördernummer -
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6524426.rdf
1000 Erstellt am 2025-07-07T04:17:17.606+0200
1000 Erstellt von 322
1000 beschreibt frl:6524426
1000 Zuletzt bearbeitet 2025-07-31T09:27:36.318+0200
1000 Objekt bearb. Thu Jul 31 09:27:36 CEST 2025
1000 Vgl. frl:6524426
1000 Oai Id
  1. oai:frl.publisso.de:frl:6524426 |
1000 Sichtbarkeit Metadaten public
1000 Sichtbarkeit Daten public
1000 Gegenstand von

View source