VA1213, a selective COX-2 inhibitor, exhibits antitumor activity by suppressing EGFR, AKT, and ERK1/2 phosphorylation
Year: 2025
Type: article
Abstract: Cyclooxygenase-2 (COX-2) is overexpressed in various cancers and has emerged as a promising target in oncological pharmacotherapy. This study investigates the in vitro antitumor properties and mechanism of action of novel vicinal diaryl-substituted heterocyclic COX-2 inhibitors, with a focus on VA1213 , in comparison to celecoxib, a widely marketed COX-2 inhibitor known for its off-target effects. We assessed cytotoxicity, apoptosis induction, cell-cycle distribution, antimetastatic activity, and alterations in key signaling pathways in HT-29 colorectal carcinoma and MDA-MB-231 breast carcinoma cell lines. Among the novel compounds, VA1213 exhibited the most potent growth-inhibitory activity, demonstrating time-dependent cytotoxicity with a lower IC 50 after 48–72 hours of treatment compared to VA692 and VA694 , and consistent with that observed for celecoxib. Unlike celecoxib, which produced rapid cytotoxic effects, VA1213 required prolonged exposure, suggesting a distinct mechanism of action. VA1213 induced G₀/G₁ phase cell cycle arrest and apoptosis via caspase-3 activation. Furthermore, it impaired EGFR downstream signaling by reducing ERK1/2 and AKT phosphorylation, without directly inhibiting EGFR itself. At sub-cytotoxic concentrations, VA1213 was more effective than celecoxib in inhibiting cell migration and demonstrated a comparable reduction in clonogenic potential. These findings highlight VA1213 as a COX-2 inhibitor with noteworthy in vitro antitumor efficacy, comparable to that of celecoxib. Its ability to interfere with multiple cancer-associated signaling pathways and reduce tumor cell aggressiveness underscores its potential as a promising therapeutic candidate. Further in vivo studies are warranted to confirm its efficacy and assess potential off-target effects.
Authors: Valerio Ciccone, Claudia Cecchin, Maria Frosini, Mario Saletti, Samuele Maramai, Germano Giuliani, Marco Paolino, Andrea Cappelli, Maurizio Anzini, Sandra Donnini, Lucia Morbidelli
Institution: University of Siena
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,070
OpenAlex ID: W4417537405