title: N-acetylcysteine potentiates doxorubicin-induced ATM and p53 activation             in ovarian cancer cells.
abstract: Doxorubicin has been used clinically to treat various types of cancer, and             yet the molecular mode of actions of doxorubicin remains to be fully unraveled.             In this study, we investigated the effect of doxorubicin on cultured ovarian cancer             cells (CaOV3). MTT assay data showed that doxorubicin inhibits cell proliferation             in a time- and dose-dependent manner. Phagokinetic cell motility assay data indicated             that doxorubicin inhibits both basal level and EGF-induced cell migration in CaOV3             cells. Confocal microscopic data revealed that doxorubicin induces reorganization             of cytoskeletal proteins including actin, tubulin and vimentin. Doxorubicin induces             phosphorylation of p53 at Ser15 and 20, acetylation of p53 and ATM activation.             Doxorubicin also induces phosphorylation of histone H2AX at Ser139. Interestingly,             doxorubicin also inhibits mTOR activity, measured by phosphorylation of S6 ribosomal             protein. Pretreatment of CaOV3 cells with antioxidant N-acetylcysteine (NAC),             but not pyrrolidine dithiocarbamate (PDTC) potentiates doxorubicin-induced phosphorylation             of p53 and ATM. Collectively, we conclude that doxorubicin induces ATM/p53 activation             leading to reorganization of cytoskeletal networks, inhibition of mTOR activity,             and inhibition of cell proliferation and migration. Our data also suggest that             removal of oxidants by antioxidants such as NAC may enhance the efficacy of doxorubicin             in vivo.
authors.affiliation: Department of Biology, Providence College, Providence, RI 02918,                     USA.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Brum
authors.forename: Thomas
authors.initials: T
authors.lastname: Carbone
authors.forename: Eric
authors.initials: E
authors.lastname: Still
authors.forename: Vendita
authors.initials: V
authors.lastname: Correia
authors.forename: Kevin
authors.initials: K
authors.lastname: Szulak
authors.forename: David
authors.initials: D
authors.lastname: Calianese
authors.forename: Charles
authors.initials: C
authors.lastname: Best
authors.forename: Garret
authors.initials: G
authors.lastname: Cammarata
authors.forename: Katelyn
authors.initials: K
authors.lastname: Higgins
authors.forename: Fang
authors.initials: F
authors.lastname: Ji
authors.forename: Wen
authors.initials: W
authors.lastname: Di
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; D006657:Histones; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000111:Acetylcysteine