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

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

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.

Maddaloni M; Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, 34149 Trieste, Italy.
Farra R; Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, 34149 Trieste, Italy.
Dapas B; Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, 34149 Trieste, Italy.
Felluga F; Department of Chemical and Pharmaceutical Sciences (DSCF), University of Trieste, 34127 Trieste, Italy.
Benedetti F; Department of Chemical and Pharmaceutical Sciences (DSCF), University of Trieste, 34127 Trieste, Italy.
Berti F; Department of Chemical and Pharmaceutical Sciences (DSCF), University of Trieste, 34127 Trieste, Italy.
Drioli S; Department of Chemical and Pharmaceutical Sciences (DSCF), University of Trieste, 34127 Trieste, Italy.
Vidali M; Department of Chemical and Pharmaceutical Sciences (DSCF), University of Trieste, 34127 Trieste, Italy.
Cemazar M; Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia.
Kamensek U; Faculty of Health Sciences, University of Primorska, Polje 42, SI-6310 Izola, Slovenia.
Brancolini C; Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia.
Murano E; Laboratory of Epigenomics, Department of Medicine, University of Udine, Piazzale Kolbe 4, 33100 Udine, Italy.
Maremonti F; Nealys S.R.L., Via Flavia 23/1, 34148 Trieste, Italy.
Grassi M; Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, 34149 Trieste, Italy.
Biasin A; Department of Engineering and Architecture, University of Trieste, Via Valerio 6/A, 34127 Trieste, Italy.
Rizzolio F; Department of Engineering and Architecture, University of Trieste, Via Valerio 6/A, 34127 Trieste, Italy.
Cavarzerani E; Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy.
Scaggiante B; Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, 30172 Venice, Italy.
Bulla R; Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, 30172 Venice, Italy.
Balduit A; Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, 34149 Trieste, Italy.
Ricci G; Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
Zito G; Institute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137 Trieste, Italy.
Romano F; Institute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137 Trieste, Italy.
Bonin S; Department of Medical, Surgical and Health Science, University of Trieste, 34129 Trieste, Italy.
Azzalini E; Institute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137 Trieste, Italy.
Baj G; Institute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137 Trieste, Italy.
Tierno D; Department of Medical, Surgical and Health Science, University of Trieste, 34129 Trieste, Italy.
Grassi G; Department of Medical, Surgical and Health Science, University of Trieste, 34129 Trieste, Italy.

Pharmaceutics ; 16(5)2024 May 15.

Article en En | MEDLINE | ID: mdl-38794326

ABSTRACT

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.