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 Full article
| Journal |
Cellular Oncology
ISSN: 22113428 |
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| Output data | Year: 2023, Pages: 1-21 Pages count : 21 DOI: 10.1007/s13402-023-00882-x | ||||||||||||||||||
| Tags | Colon Cancer · Epigenetic · Histone Deacetylase Inhibitor · Copper Complex · Organoids | ||||||||||||||||||
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Abstract:
Purpose 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), in vitro and ex vivo, designed to overcome the pharmacokinetic challenges of belinostat.
Methods The in vitro metabolism of each HDACi was evaluated in human liver microsomes (HLMs) using mass spectrometry.
Next, the efect 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
in silico analysis to identify master regulators (MRs) of diferentially expressed genes (DEGs). The efect of both HDACis
on the viability of colon cancer patient-derived tumor organoids (PDTOs) was also examined.
Results Belinostat and Cubisbel signifcantly reduced colon cancer cell growth mediated through HDAC inhibition and
apoptosis induction. Interestingly, the in vitro half-life of Cubisbel was signifcantly longer than belinostat. Belinostat and its
Cu derivative commonly dysregulated numerous signalling and metabolic pathways while genes downregulated by Cubisbel
were potentially controlled by VEGFA, ERBB2 and DUSP2 MRs. Treatment of colon cancer PDTOs with the HDACis
resulted in a signifcant reduction in cell viability and downregulation of stem cell and proliferation markers.
Conclusions Complexation of belinostat to Cu(II) does not alter the HDAC activity of belinostat, but instead signifcantly
enhances its metabolic stability in vitro and targets anti-cancer pathways by perturbing key MRs in colon cancer. Complexation
of HDACis to a metal ion might improve the efcacy of clinically used HDACis in patients with colon cancer.
Cite:
Finnegan E.
, Ding W.
, Ude Z.
, Terer S.
, McGivern T.
, Blümel A.M.
, Kirwan G.
, Shao X.
, Genua F.
, Yin X.
, Kel A.
, Fattah S.
, Myer P.A.
, Cryan S-A.
, Prehn J.H.M.
, O’Connor D.P.
, Brennan L.
, Yochum G.
, Marmion C.J.
, Das S.
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
Cellular Oncology. 2023. P.1-21. DOI: 10.1007/s13402-023-00882-x WOS Scopus OpenAlex
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
Cellular Oncology. 2023. P.1-21. DOI: 10.1007/s13402-023-00882-x WOS Scopus OpenAlex
Dates:
| Published online: | Nov 7, 2023 |
Identifiers:
| Web of science: | WOS:001100148600001 |
| Scopus: | 2-s2.0-85175984768 |
| OpenAlex: | W4388455477 |