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The present study investigated the in vitro effects of liposomal aluminum-phthalocyanine chloride (AlPc)-based Photodynamic Therapy (PDT) on PI3K/Akt/mTOR signaling pathway, which has been reported to be constantly activated in squamous cell carcinoma. Cultured cells derived from Oral Squamous Cell Carcinoma (OSCC-3 lineage) were used. PDT was applied in vitro by exposing cultured cells to liposomal AlPc (0.5 or 2.5 μM for 30 minutes) and then irradiating them with laser (670 nm wavelengths, 24 J/cm2 energy density). Cell viability was assessed by tripan blue staining and MTT assay. DNA fragmentation and mitochondrial permeability, signs of apoptosis, were also evaluated. Inhibition of PI3K/AKT/mTOR was accessed by immunofluorescence assay for detection of pS6, a downstream phosphorylated protein of this signaling pathway, in confocal microscopy. Morphological analysis was performed by FACS scan and phase contrast microscopy. Different mechanisms of cell death were induced in OSCC-3 cells, mainly apoptosis. Moreover, PI3K/Akt/mTOR signaling pathway was inhibited. The results show that cell death induced by AlPc-based PDT involves, at least partially, inhibition of the PI3K/Akt/mTOR pathway.