CANDESARTAN CILEXETIL AS A REPURPOSED THERAPEUTIC CANDIDATE FOR NASOPHARYNGEAL CARCINOMA: INTEGRATED IN VITRO AND IN SILICO ANALYSES

Abstract

Nasopharyngeal carcinoma (NPC) is prevalent in East and Southeast Asia and is often diagnosed at advanced stages, where current treatment options are limited and associated with high relapse rates and toxicity. Repurposing clinically approved drugs provides a rapid, cost-effective strategy to identify new therapeutic interventions. Here, we investigated candesartan cilexetil (CC), an angiotensin II type 1 receptor (AT1R) blocker widely used for hypertension (13), for its potential anti-cancer effects in NPC. In vitro assays were performed to assess cell via-bility, proliferation, clonogenic survival, migration, cell-cycle distribution, and epithelial-mesenchymal transition (EMT) marker expression. Molecular mechanisms were examined via immunoblotting of AT1R and downstream MAPK and PI3K-AKT pathways. In silico molecular dynamics (MD) simulations were conducted to characterize CC-AT1R binding. We found that CC significantly decreased NPC cell viability and proliferation in a concentra-tion-dependent manner, while exhibiting lower cytotoxicity toward immortalized nasopharyngeal epithelial cells. CC inhibited colony formation, induced G0/G1 cell-cycle arrest, and suppressed migration. EMT markers were differentially regulated, with consistent downregulation of vimentin and Slug but paradoxical cadherin changes, indicating context-dependent EMT modulation. Mechanistically, CC downregulated AT1R expression, reduced phosphorylation of p38 MAPK, and enhanced AKT phosphorylation, suggesting compensatory survival signaling. MD simulations confirmed stable CC-AT1R binding, identifying key residues critical for ligand stabilization. Therefore, CC exerts multi-faceted inhibitory effects on NPC cells through AT1R blockade and downstream modulation of oncogenic pathways. The integration of in vitro and in silico analyses highlights CC as a promising repurposed therapeutic candidate for NPC and supports further preclinical evaluation.