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

Ellen Finnegan; Wei Ding; Ziga Ude; Sara Terer; Tadhg McGivern; Anna M. Blümel; Grainne Kirwan; Xinxin Shao; Flavia Genua; Xiaofei Yin; Alexander Kel; Sarinj Fattah; Parvathi A. Myer; Sally Ann Cryan; Jochen H.M. Prehn; Darran P. O’Connor; Lorraine Brennan; Gregory Yochum; Celine J. Marmion; Sudipto Das

doi:10.1007/s13402-023-00882-x

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

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

Medicine

Research output: Contribution to journal › Article › peer-review

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 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 in silico 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. Results: Belinostat and Cubisbel significantly reduced colon cancer cell growth mediated through HDAC inhibition and apoptosis induction. Interestingly, the in vitro 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 VEGFA, ERBB2 and DUSP2 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. Conclusions: Complexation of belinostat to Cu(II) does not alter the HDAC activity of belinostat, but instead significantly 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 efficacy of clinically used HDACis in patients with colon cancer.

Original language	English (US)
Journal	Cellular oncology (Dordrecht)
DOIs	https://doi.org/10.1007/s13402-023-00882-x
State	Accepted/In press - 2023

Keywords

Colon Cancer
Copper Complex
Epigenetic
Histone Deacetylase Inhibitor
Organoids

ASJC Scopus subject areas

Molecular Medicine
Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s13402-023-00882-x

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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. (Accepted/In press). 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 (Dordrecht). https://doi.org/10.1007/s13402-023-00882-x

Finnegan, E, Ding, W, Ude, Z, Terer, S, McGivern, T, Blümel, AM, Kirwan, G, Shao, X, Genua, F, Yin, X, Kel, A, Fattah, S, Myer, PA, Cryan, SA, Prehn, JHM, O’Connor, DP, Brennan, L, Yochum, G, Marmion, CJ & Das, S 2023, '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 (Dordrecht). https://doi.org/10.1007/s13402-023-00882-x

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title = "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",

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 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 in silico 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. Results: Belinostat and Cubisbel significantly reduced colon cancer cell growth mediated through HDAC inhibition and apoptosis induction. Interestingly, the in vitro 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 VEGFA, ERBB2 and DUSP2 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. Conclusions: Complexation of belinostat to Cu(II) does not alter the HDAC activity of belinostat, but instead significantly 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 efficacy of clinically used HDACis in patients with colon cancer.",

keywords = "Colon Cancer, Copper Complex, Epigenetic, Histone Deacetylase Inhibitor, Organoids",

author = "Ellen Finnegan and Wei Ding and Ziga Ude and Sara Terer and Tadhg McGivern and Bl{\"u}mel, {Anna M.} and Grainne Kirwan and Xinxin Shao and Flavia Genua and Xiaofei Yin and Alexander Kel and Sarinj Fattah and Myer, {Parvathi A.} and Cryan, {Sally Ann} and Prehn, {Jochen H.M.} and O{\textquoteright}Connor, {Darran P.} and Lorraine Brennan and Gregory Yochum and Marmion, {Celine J.} and Sudipto Das",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

doi = "10.1007/s13402-023-00882-x",

language = "English (US)",

journal = "Cellular oncology (Dordrecht)",

issn = "2211-3428",

publisher = "Springer Netherlands",

}

TY - JOUR

T1 - 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

AU - Finnegan, Ellen

AU - Ding, Wei

AU - Ude, Ziga

AU - Terer, Sara

AU - McGivern, Tadhg

AU - Blümel, Anna M.

AU - Kirwan, Grainne

AU - Shao, Xinxin

AU - Genua, Flavia

AU - Yin, Xiaofei

AU - Kel, Alexander

AU - Fattah, Sarinj

AU - Myer, Parvathi A.

AU - Cryan, Sally Ann

AU - Prehn, Jochen H.M.

AU - O’Connor, Darran P.

AU - Brennan, Lorraine

AU - Yochum, Gregory

AU - Marmion, Celine J.

AU - Das, Sudipto

PY - 2023

Y1 - 2023

N2 - 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 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 in silico 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. Results: Belinostat and Cubisbel significantly reduced colon cancer cell growth mediated through HDAC inhibition and apoptosis induction. Interestingly, the in vitro 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 VEGFA, ERBB2 and DUSP2 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. Conclusions: Complexation of belinostat to Cu(II) does not alter the HDAC activity of belinostat, but instead significantly 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 efficacy of clinically used HDACis in patients with colon cancer.

AB - 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 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 in silico 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. Results: Belinostat and Cubisbel significantly reduced colon cancer cell growth mediated through HDAC inhibition and apoptosis induction. Interestingly, the in vitro 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 VEGFA, ERBB2 and DUSP2 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. Conclusions: Complexation of belinostat to Cu(II) does not alter the HDAC activity of belinostat, but instead significantly 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 efficacy of clinically used HDACis in patients with colon cancer.

KW - Colon Cancer

KW - Copper Complex

KW - Epigenetic

KW - Histone Deacetylase Inhibitor

KW - Organoids

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U2 - 10.1007/s13402-023-00882-x

DO - 10.1007/s13402-023-00882-x

M3 - Article

AN - SCOPUS:85175984768

SN - 2211-3428

JO - Cellular oncology (Dordrecht)

JF - Cellular oncology (Dordrecht)

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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