Details
- Autor(en) / Beteiligte
- Titel
- Chemotherapeutic sensitization of leptomycin B resistant lung cancer cells by pretreatment with doxorubicin
- Ist Teil von
- PloS one, 2012-03, Vol.7 (3), p.e32895
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The development of novel targeted therapies has become an important research focus for lung cancer treatment. Our previous study has shown leptomycin B (LMB) significantly inhibited proliferation of lung cancer cells; however, p53 wild type lung cancer cells were resistant to LMB. Therefore, the objective of this study was to develop and evaluate a novel therapeutic strategy to sensitize LMB-resistant lung cancer cells by combining LMB and doxorubicin (DOX). Among the different treatment regimens, pretreatment with DOX (pre-DOX) and subsequent treatment with LMB to A549 cells significantly decreased the 50% inhibitory concentration (IC50) as compared to that of LMB alone (4.4 nM vs. 10.6 nM, P<0.05). Analysis of cell cycle and apoptosis by flow cytometry further confirmed the cytotoxic data. To investigate molecular mechanisms for this drug combination effects, p53 pathways were analyzed by Western blot, and nuclear proteome was evaluated by two dimensional-difference gel electrophoresis (2D-DIGE) and mass spectrometry. In comparison with control groups, the levels of p53, phospho-p53 (ser15), and p21 proteins were significantly increased while phospho-p53 (Thr55) and survivin were significantly decreased after treatments of pre-DOX and LMB (P<0.05). The 2D-DIGE/MS analysis identified that sequestosome 1 (SQSTM1/p62) had a significant increase in pre-DOX and LMB-treated cells (P<0.05). In conclusion, our results suggest that drug-resistant lung cancer cells with p53 wild type could be sensitized to cell death by scheduled combination treatment of DOX and LMB through activating and restoring p53 as well as potentially other signaling pathway(s) involving sequestosome 1.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0032895Titel-ID: cdi_plos_journals_1323981938
- Format
- –
- Schlagworte
- Amino Acid Sequence, Anthracyclines, Antineoplastic Agents - pharmacology, Antineoplastic Agents - toxicity, Apoptosis, Apoptosis - drug effects, Autophagy, Biology, Cancer, Cancer cells, Cancer therapies, Cell cycle, Cell Cycle - drug effects, Cell death, Cell Line, Tumor, Cell proliferation, Chemistry, Chemotherapy, Combination drug therapy, Comparative analysis, Cyclin-Dependent Kinase Inhibitor p21 - metabolism, Cytometry, Cytotoxicity, Deoxyribonucleic acid, DNA, DNA repair, Doxorubicin, Doxorubicin - pharmacology, Doxorubicin - toxicity, Drug resistance, Drug Resistance, Neoplasm - drug effects, Drug therapy, Combination, Fatty Acids, Unsaturated - pharmacology, Fatty Acids, Unsaturated - toxicity, Flow cytometry, Gel electrophoresis, Gene expression, Health aspects, Health sciences, Humans, Inhibitor of Apoptosis Proteins - metabolism, Internal medicine, Leptomycin B, Leukemia, Lung cancer, Lung diseases, Lung Neoplasms - drug therapy, Lung Neoplasms - metabolism, Lymphocytes B, Mass spectrometry, Mass spectroscopy, Medical prognosis, Medicine, Molecular modelling, Molecular Sequence Data, Nuclear Proteins - metabolism, p53 Protein, Phosphorylation, Pretreatment, Proteins, Proteomes, Proteomics - methods, Respiratory agents, Respiratory system agents, Signal transduction, Signaling, Studies, Survivin, Toxicology, Tumor proteins, Tumor Suppressor Protein p53 - metabolism, Two dimensional analysis