N-acetylcysteine potentiates doxorubicin-induced ATM and p53 activation in ovarian cancer cells

Autor: Yinsheng Wan, Kevin Szulak, Fang Ji, Gabriella Brum, Thomas Carbone, Eric Still, Charles Best, Vendita Correia, Katelyn Higgins, Garret Cammarata, David Calianese, Wen Di
Rok vydání: 2012
Předmět:
p53
Cancer Research
Cell
Cell Cycle Proteins
Ataxia Telangiectasia Mutated Proteins
Protein Serine-Threonine Kinases
Biology
doxorubicin
Histones
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Pyrrolidine dithiocarbamate
Tumor Cells
Cultured
polycyclic compounds
medicine
Humans
MTT assay
Doxorubicin
PI3K/AKT/mTOR pathway
030304 developmental biology
Ovarian Neoplasms
0303 health sciences
Antibiotics
Antineoplastic
Cell growth
Tumor Suppressor Proteins
Drug Synergism
Free Radical Scavengers
Articles
Cell cycle
N-acetylcysteine
Acetylcysteine
3. Good health
Cell biology
DNA-Binding Proteins
Cytoskeletal Proteins
ovarian cancer
medicine.anatomical_structure
Oncology
chemistry
ATM
030220 oncology & carcinogenesis
Cancer research
Phosphorylation
Female
Tumor Suppressor Protein p53
medicine.drug
Zdroj: International Journal of Oncology
ISSN: 1791-2423
1019-6439
DOI: 10.3892/ijo.2012.1680
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: