Fluoxetine Suppresses Osteosarcoma Progression In Vivo by Inducing Apoptosis and Inhibiting the AKT/mTOR/NF-κB Signaling Pathway.

Abstract

Background/aim: Osteosarcoma (OSCC) remains a significant health concern, necessitating novel therapeutic strategies. This study investigated the anti-tumor effects of fluoxetine in an in vivo OSCC model.

Materials and methods: Mice inoculated with U-2 OS cells were treated with fluoxetine (10 or 20 mg/kg) to evaluate tumor growth, metastasis, and underlying molecular mechanisms.

Results: Fluoxetine treatment resulted in a dose-dependent reduction in tumor volume and weight, without causing systemic toxicity, as confirmed by histopathological and biochemical analyses. Mechanistically, fluoxetine activated caspase-dependent apoptosis by up-regulating cleaved caspase-8, caspase-9, and caspase-3. It also inhibited OSCC metastasis by suppressing VEGF and MMP-9 expression, reducing epithelial-mesenchymal transition markers. Furthermore, fluoxetine significantly reduced the phosphorylation of AKT, PRAS40, mTOR, and NF-[Formula: see text]B, thereby disrupting key tumorigenic signaling pathways.

Conclusion: Fluoxetine demonstrates promising anti-tumor activity in OSCC by inducing apoptosis, inhibiting metastasis, and targeting oncogenic signaling pathways. These findings suggest that fluoxetine may serve as a potential therapeutic agent for OSCC, warranting further investigation for clinical application.