Hydrophobic Phenoxazines Shut Down PI3K/Akt/mTOR/P70S6/S6 Kinase Signalling Pathway and Induces Massive Apoptosis in Rhabdomyosarcoma Cells

Akt plays an important role in many types of cancers and has been identified as a therapeutic target. Several types of cancers have posed a major threat to human health. Conventional treatments suffer from limitations of side effects, poor responses and drugresistance. Phenoxazines have shown diverse biological activities and promising agents in anti-cancer, anti-viral and antibacterial therapy. In this study, we evaluated the effect of phenoxazine derivatives on rhabdomyosarcoma cells. Hydrophobic phenoxazines shut down Akt/mTOR/p70S6/S6 kinase pathway and induce apoptosis in rhabdomyosarcoma cells. There is activation of Akt pathway in rhabdomyosarcoma cell lines which have tumorigenic potential. These cell lines are sensitive to phenoxazines. The phenoxazine derivatives are compared for their ability to inhibit Akt phosphorylation in these cells. The lipophilicity of these compounds increased significantly by increasing the chain length to (-CH2)5 or (-CH2)6 from the corresponding (-CH2)3 or (-CH2)4 at N10 -position of the phenoxazine ring. The ability of various phenoxazine derivatives to inhibit Akt phosphorylation in rhabdomyosarcoma cells follows the order: N10-hexyl > N10-pentyl > N10-butyl > N10-propyl. Within the series, -Cl in C-2 position on the phenoxazine ring demonstrated a higher potency compared to phenoxazines with –H in C-2 position, suggesting that chlorine is playing a critical role on the growth inhibition.