Open AccessHydrophobic Phenoxazines Shut Down PI3K/Akt/mTOR/P70S6/S6 Kinase Signalling Pathway and Induces Massive Apoptosis in Rhabdomyosarcoma Cells
Author(s) -
B. Sridhar,
M. N. Kumara,
T Padma,
Κ. N. Thimmaiah,
Houghton PJ
Publication year - 2021
Publication title -
international journal of pharmaceutical sciences review and research
Language(s) - English
Resource type - Journals
ISSN - 0976-044X
DOI - 10.47583/ijpsrr.2021.v71i02.017
Subject(s) - phenoxazine , pi3k/akt/mtor pathway , protein kinase b , rhabdomyosarcoma , chemistry , cancer research , apoptosis , cell growth , kinase , cell culture , biochemistry , pharmacology , biology , medicine , sarcoma , genetics , pathology , phenothiazine
Akt plays an important role in many types of cancers and has been identified as a therapeutic target. Several types of cancers haveposed 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 antibacterialtherapy. In this study, we evaluated the effect of phenoxazine derivatives on rhabdomyosarcoma cells. Hydrophobic phenoxazinesshut down Akt/mTOR/p70S6/S6 kinase pathway and induce apoptosis in rhabdomyosarcoma cells. There is activation of Akt pathwayin rhabdomyosarcoma cell lines which have tumorigenic potential. These cell lines are sensitive to phenoxazines. The phenoxazinederivatives are compared for their ability to inhibit Akt phosphorylation in these cells. The lipophilicity of these compounds increasedsignificantly by increasing the chain length to (-CH2)5 or (-CH2)6 from the corresponding (-CH2)3 or (-CH2)4 at N10-position of thephenoxazine ring. The ability of various phenoxazine derivatives to inhibit Akt phosphorylation in rhabdomyosarcoma cells followsthe order: N10-hexyl > N10-pentyl > N10-butyl > N10-propyl. Within the series, -Cl in C-2 position on the phenoxazine ring demonstrateda higher potency compared to phenoxazines with –H in C-2 position, suggesting that chlorine is playing a critical role on the growthinhibition.