Journal
ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY
Volume 15, Issue 10, Pages 1297-1304Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1871520615666150402093558
Keywords
Apoptosis; 6-(4-phenoxyphenyl)-N-phenylquinolin-4-amine [PQQ]; PI3K-Akt-mTOR
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Funding
- UGC, New Delhi, India
- Council of Scientific and Industrial Research (CSIR), New Delhi, India
- CSIR 12th five-year project [BSC0108, BSC-0205]
- IIIM communication [IIIM/1713/2014]
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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 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 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.
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