Maddaloni, Marianna and Farra, Rossella and Dapas, Barbara and Felluga, Fulvia and Benedetti, Fabio and Berti, Federico and Drioli, Sara and Vidali, Mattia and Cemazar, Maja and Kamensek, Urska and Brancolini, Claudio and Murano, Erminio and Maremonti, Francesca and Grassi, Mario and Biasin, Alice and Rizzolio, Flavio and Cavarzerani, Enrico and Scaggiante, Bruna and Bulla, Roberta and Balduit, Andrea and Ricci, Giuseppe and Zito, Gabriella and Romano, Federico and Bonin, Serena and Azzalini, Eros and Baj, Gabriele and Tierno, Domenico and Grassi, Gabriele (2024) In Vitro and In Vivo Evaluation of the Effects of Drug 2c and Derivatives on Ovarian Cancer Cells. PHARMACEUTICS, 16 (5): 664. ISSN , 1999-4923
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ; ovarian cancer; 2C; apoptosis; in silico docking |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Immunologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 21 Aug 2025 08:37 |
| Last Modified: | 21 Aug 2025 08:37 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65503 |
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