Imipramine Targets Apoptosis, Metastasis, and EGFR/SRC-mediated EMT in Oral Cancer Cells

Background/Aim: Oral cancer (OC) exhibits aggressive growth and metastatic potential. Imipramine, a tricyclic antidepressant, has been recently explored for its anticancer activity. This study investigated imipramine’s therapeutic effects and underlying anti-progression mechanisms in OC.

Materials and Methods: SAS and MOC1 cell lines were treated with imipramine for cytotoxicity, apoptosis, migration, invasion, and epithelial–mesenchymal transition (EMT) analyses using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, Transwell assays, and western blotting.

Results: Imipramine significantly reduced OC cell viability in a dose-dependent manner and induced apoptosis through both extrinsic (Fas/FasL–caspase-8) and intrinsic (mitochondrial depolarization, ROS/Ca²⁺ elevation, caspase-9) pathways. Anti-apoptotic proteins X-linked inhibitor of apoptosis (XIAP) and cellular FLICE-like inhibitory protein (c-FLIP) and proliferation regulator Cyclin D1 were downregulated. Imipramine also inhibited migration, invasion, and expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor-A (VEGF-A). EMT progression was suppressed, evidenced by decreased zinc-finger-enhancer binding protein 1/2 (ZEB1/2), Snail, Slug, N-cadherin, and re-expression of E-cadherin, accompanied by inactivation of the EGFR/SRC axis.

Conclusion: Imipramine exhibits potent anti-OC activity by inducing apoptosis, inhibiting metastasis, and suppressing EMT, supporting its potential as a repurposed therapeutic agent.