药物2c及其衍生物对卵巢癌细胞作用的体外和体内评价

In Vitro and In Vivo Evaluation of the Effects of Drug 2c and Derivatives on Ovarian Cancer Cells.

作者信息

Maddaloni Marianna, Farra Rossella, Dapas Barbara, Felluga Fulvia, Benedetti Fabio, Berti Federico, Drioli Sara, Vidali Mattia, Cemazar Maja, Kamensek Urska, Brancolini Claudio, Murano Erminio, Maremonti Francesca, Grassi Mario, Biasin Alice, Rizzolio Flavio, Cavarzerani Enrico, Scaggiante Bruna, Bulla Roberta, Balduit Andrea, Ricci Giuseppe, Zito Gabriella, Romano Federico, Bonin Serena, Azzalini Eros, Baj Gabriele, Tierno Domenico, Grassi Gabriele

机构信息

Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, 34149 Trieste, Italy.

Department of Chemical and Pharmaceutical Sciences (DSCF), University of Trieste, 34127 Trieste, Italy.

出版信息

Pharmaceutics. 2024 May 15;16(5):664. doi: 10.3390/pharmaceutics16050664.

DOI:10.3390/pharmaceutics16050664

PMID:38794326

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11125437/

Abstract

BACKGROUND

The identification of novel therapeutic strategies for ovarian cancer (OC), the most lethal gynecological neoplasm, is of utmost urgency. Here, we have tested the effectiveness of the compound 2c (4-hydroxy-2,6-bis(4-nitrobenzylidene)cyclohexanone 2). 2c interferes with the cysteine-dependent deubiquitinating enzyme (DUB) UCHL5, thus affecting the ubiquitin-proteasome-dependent degradation of proteins.

METHODS

2c phenotypic/molecular effects were studied in two OC 2D/3D culture models and in a mouse xenograft model. Furthermore, we propose an in silico model of 2c interaction with DUB-UCHL5. Finally, we have tested the effect of 2c conjugated to several linkers to generate 2c/derivatives usable for improved drug delivery.

RESULTS

2c effectively impairs the OC cell line and primary tumor cell viability in both 2D and 3D conditions. The effectiveness is confirmed in a xenograft mouse model of OC. We show that 2c impairs proteasome activity and triggers apoptosis, most likely by interacting with DUB-UCHL5. We also propose a mechanism for the interaction with DUB-UCHL5 via an in silico evaluation of the enzyme-inhibitor complex. 2c also reduces cell growth by down-regulating the level of the transcription factor E2F1. Eventually, 2c activity is often retained after the conjugation with linkers.

CONCLUSION

Our data strongly support the potential therapeutic value of 2c/derivatives in OC.

摘要

背景

卵巢癌（OC）是最致命的妇科肿瘤，确定其新的治疗策略迫在眉睫。在此，我们测试了化合物2c（4-羟基-2,6-双（4-硝基亚苄基）环己酮2）的有效性。2c干扰半胱氨酸依赖性去泛素化酶（DUB）UCHL5，从而影响蛋白质的泛素-蛋白酶体依赖性降解。

方法

在两种OC二维/三维培养模型和小鼠异种移植模型中研究了2c的表型/分子效应。此外，我们提出了2c与DUB-UCHL5相互作用的计算机模拟模型。最后，我们测试了与几种连接子偶联的2c的效果，以生成可用于改善药物递送的2c/衍生物。

结果

在二维和三维条件下，2c均有效损害OC细胞系和原发性肿瘤细胞的活力。在OC的异种移植小鼠模型中证实了其有效性。我们表明，2c可能通过与DUB-UCHL5相互作用来损害蛋白酶体活性并触发细胞凋亡。我们还通过对酶-抑制剂复合物的计算机模拟评估，提出了与DUB-UCHL5相互作用的机制。2c还通过下调转录因子E2F1的水平来减少细胞生长。最终，与连接子偶联后，2c的活性通常得以保留。