Amiloride may also induce the dephosphorylation (inactivation) of Akt through the inhibition of PI3 K, resulting in cytotoxicity mediated by TRAIL (tumor necrosis factor-related apoptosis-ligand), which may be related to the increased expression of p53 within the cytosol, the upregulation of the pro-apoptotic protein Bax, and the downregulation of the anti-apoptotic protein Bcl-xL, as demonstrated in canine osteosarcoma cell lines [93,94]. Here, AKT1 is linked to osteosarcoma.