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.

IF 4.9 2区医学 Q2 CELL BIOLOGY

Cellular Oncology Pub Date : 2024-04-01 Epub Date: 2023-11-07 DOI:10.1007/s13402-023-00882-x

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

{"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.","authors":"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","DOIUrl":null,"url":null,"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.","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"533-553"},"PeriodicalIF":4.9000,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090832/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13402-023-00882-x","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/11/7 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

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.

Abstract Image

查看原文本刊更多论文

组蛋白去乙酰化酶抑制剂贝利那司坦与Cu（II）的络合可防止体外过早代谢失活，并在癌症体内外显示出强大的抗癌活性。

目的：组蛋白脱乙酰酶抑制剂（HDACi）贝利诺司他由于代谢稳定性差，在实体瘤如癌症中的治疗效果有限。在这里，我们在体外和离体评估了一种新的贝利诺司他前药，铜双贝利诺司他（Cubisbel），旨在克服贝利诺司特的药代动力学挑战。方法：采用质谱法在人肝微粒体（HLMs）中评价每种HDACi的体外代谢。接下来，在三种癌症细胞系中评估贝利诺司他和库比司贝尔对细胞生长、HDAC活性、细胞凋亡和细胞周期的影响。使用RNA-Seq测定两种HDACis诱导的基因表达改变，然后进行计算机分析以鉴定差异表达基因（DEG）的主调节因子（MR）。还检测了两种HDACis对癌症患者来源的肿瘤类器官（PDTO）生存能力的影响。结果：Belinostat和Cubisbel通过抑制HDAC和诱导细胞凋亡介导的结肠癌细胞生长显著降低。有趣的是，Cubisbel的体外半衰期明显长于belinostat。Belinostat及其Cu衍生物通常失调许多信号传导和代谢途径，而Cubisbel下调的基因可能受VEGFA、ERBB2和DUSP2MRs的控制。用HDACis治疗结肠癌癌症PDTO导致细胞活力显著降低，干细胞和增殖标志物下调。结论：belinostat与Cu（II）的络合不会改变belinostat的HDAC活性，而是显著增强其体外代谢稳定性，并通过干扰癌症中的关键MR来靶向抗癌途径。HDACis与金属离子的络合可能提高临床使用的HDACis在癌症患者中的疗效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cellular Oncology ONCOLOGY-CELL BIOLOGY

CiteScore

10.30

自引率

1.50%

发文量

审稿时长

12 months

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.