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

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

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

Authors

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

Affiliations

1	School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
2	Department of Surgery, Division of Colon & Rectal Surgery, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, USA
3	Department of Chemistry, RCSI University of Medicine and Health Sciences, Dublin, Ireland
4	Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
5	UCD School of Agriculture and Food Science, UCD Conway Institute, Belfield, University College Dublin, Dublin, Ireland
6	BIOSOFT.RU, LLC, Novosibirsk, Russia
7	GeneXplain GmbH, Wolfenbuettel, Germany
8	Institute of Chemical Biology and Fundamental Medicine SBRAS, Novosibirsk, Russia
9	Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, USA

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.

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

Published online:

Nov 7, 2023

Web of science:	WOS:001100148600001
Scopus:	2-s2.0-85175984768
OpenAlex:	W4388455477

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