title: A Novel Quinoline Based Second-generation mTOR Inhibitor that Induces Apoptosis and Disrupts PI3K-Akt-mTOR Signaling in Human Leukemia HL-60 Cells.
abstract: Deregulation of the PI3K-Akt-mTOR pathway is unanimously pragmatic in a number of tumors. This pathway pedals proliferation, survival, translation, and coupled with tumor-associated endurance. Current efforts focus on the discovery and development of novel inhibitors of this pathway. We have discovered 6-(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 second-generation 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.
authors.forename: Suresh
authors.initials: S
authors.lastname: Kumar
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Guru
authors.forename: Vunnam
authors.initials: V
authors.lastname: Venkateswarlu
authors.forename: Fayaz
authors.initials: F
authors.lastname: Malik
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.forename: Sanghapal D
authors.initials: SD
authors.lastname: Sawant
authors.affiliation: Senior Scientist, Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Canal Road, Jammu, 180001 India. sbhushan@iiim.ac.in.
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human