title: Repurposing of nitroxoline as a potential anticancer agent against human prostate cancer: a crucial role on AMPK/mTOR signaling pathway and the interplay with Chk2 activation.
abstract: Nitroxoline is an antibiotic by chelating Zn2+ and Fe2+ from biofilm matrix. In this study, nitroxoline induced G1 arrest of cell cycle and subsequent apoptosis in prostate cancer cells through ion chelating-independent pathway. It decreased protein levels of cyclin D1, Cdc25A and phosphorylated Rb, but activated AMP-activated protein kinase (AMPK), a cellular energy sensor and signal transducer, leading to inhibition of downstream mTOR-p70S6K signaling. Knockdown of AMPKα significantly rescued nitroxoline-induced inhibition of cyclin D1-Rb-Cdc25A axis indicating AMPK-dependent mechanism. However, cytoprotective autophagy was simultaneously evoked by nitroxoline. Comet assay and Western blot analysis demonstrated DNA damaging effect and activation of Chk2 other than Chk1 to nitroxoline action. Instead of serving as a DNA repair transducer, nitroxoline-mediated Chk2 activation was identified to function as a pro-apoptotic inducer. In conclusion, the data suggest that nitroxoline induces anticancer activity through AMPK-dependent inhibition of mTOR-p70S6K signaling pathway and cyclin D1-Rb-Cdc25A axis, leading to G1 arrest of cell cycle and apoptosis. AMPK-dependent activation of Chk2, at least partly, contributes to apoptosis. The data suggest the potential role of nitroxoline for therapeutic development against prostate cancers.
authors.affiliation: The Division of Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.|School of Pharmacy, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Chang
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Lih-Ching
authors.initials: LC
authors.lastname: Hsu
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Wohn-Jenn
authors.initials: WJ
authors.lastname: Leu
authors.affiliation: The Division of Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D058492:Drug Repositioning; D004789:Enzyme Activation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D009600:Nitroquinolines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009600:Nitroquinolines; D016160:Retinoblastoma Protein; D019938:Cyclin D1; C005308:nitroxoline; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases
keywords: AMPK/mTOR signaling; Chk2; Cyclin D1-Rb-Cdc25A axis; G1 arrest; Nitroxoline