VA1213, a selective COX-2 inhibitor, exhibits antitumor activity by suppressing EGFR, AKT, and ERK1/2 phosphorylation
Valerio Ciccone1, Claudia Cecchin1, Maria Frosini1
1Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena I-53100, Italy.
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 IC50 after 48-72 h 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.
Insights
Novel cyclooxygenase-2 (COX-2) inhibitor VA1213 shows potent in vitro antitumor activity against colorectal and breast cancer cells. It induces apoptosis and cell cycle arrest, offering a promising therapeutic candidate with distinct mechanisms from celecoxib.
Area of Science:
- Pharmacology
- Oncology
- Medicinal Chemistry
Background:
- Cyclooxygenase-2 (COX-2) overexpression is implicated in various cancers, making it a key therapeutic target.
- Existing COX-2 inhibitors like celecoxib have known off-target effects, necessitating the development of novel agents.
- Vicinal diaryl-substituted heterocyclic compounds represent a new class of potential COX-2 inhibitors.
Purpose of the Study:
- To evaluate the in vitro antitumor properties and mechanism of action of novel COX-2 inhibitors, focusing on VA1213.
- To compare the efficacy and cellular effects of VA1213 against celecoxib in colorectal and breast cancer cell lines.
- To investigate VA1213's impact on cell proliferation, apoptosis, cell cycle, metastasis, and key signaling pathways.
Main Methods:
- In vitro assessment of cytotoxicity, apoptosis induction, and cell-cycle distribution in HT-29 and MDA-MB-231 cell lines.
- Evaluation of antimetastatic activity, including cell migration and clonogenic potential, at sub-cytotoxic concentrations.
- Analysis of alterations in epidermal growth factor receptor (EGFR) downstream signaling pathways (ERK1/2, AKT phosphorylation).
Main Results:
- VA1213 demonstrated potent, time-dependent growth inhibition with lower IC50 values after prolonged exposure compared to shorter exposure.
- VA1213 induced G0/G1 cell cycle arrest and apoptosis via caspase-3 activation, distinct from celecoxib's rapid cytotoxic effects.
- VA1213 effectively inhibited cell migration and reduced clonogenic potential, while impairing EGFR downstream signaling without direct EGFR inhibition.
Conclusions:
- VA1213 exhibits significant in vitro antitumor efficacy comparable to celecoxib, targeting multiple cancer-associated signaling pathways.
- Its distinct mechanism of action, including delayed cytotoxicity and interference with EGFR signaling, suggests potential for reduced off-target effects.
- VA1213 represents a promising therapeutic candidate for cancer treatment, warranting further in vivo investigation for efficacy and safety.
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