A Novel Quinoline Based Second-generation mTOR Inhibitor that Induces Apoptosis and Disrupts PI3K-Akt-mTOR Signaling in Human Leukemia HL-60 Cells

Аннотация

Deregulation of the PI3K-Akt-mTOR pathway is unanimously pragmatic in a number of tumors. This pathway pedals proliferation, survival, translation, and coupled with tumorassociated endurance. Current efforts focus on the discovery and development of novel inhibitors of this pathway. We have discovered6-(4-phenoxyphenyl)-N-phenylquinolin-4-amine [PQQ] as a potent mTOR inhibitor with IC50 value of 64nM in a cell-based and cell-free mTOR assay. Mechanistically, PQQ was found to be a strong PI3K-Akt-mTOR-p70S6K cascade inhibitor in Human promyelocytic leukemia HL-60 cells. Moreover, it was found to be dual mTORC1 and mTORC2 inhibitor that inhibit the entire mTOR kinase-dependent functions and feedback commencement of PI3K/Akt pathway. PQQ simultaneously induces apoptosis via mitochondrial dependant pathway, which was confirmed through a battery of the assays, e.g. cellular and nuclear microscopy, annexin-V assay, cell cycle analysis and loss of mitochondrial membrane potential. In summary, PQQ discovered as a novel secondgeneration mTOR inhibitor with significant cytotoxic and apoptotic potentials. Thus, it might be a significant lead structure for the development of mTOR-targeted based anti-cancer therapeutics.