Document Detail


Imatinib mesylate (STI571) enhances amrubicin-induced cytotoxic activity through inhibition of the phosphatidylinositol 3-kinase/Akt pathway in small cell lung cancer cells.
MedLine Citation:
PMID:  19956885     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Small cell lung cancer (SCLC) is characterized by autocrine mechanisms. Stem cell factor (SCF) and its receptor c-kit can activate Akt and extracellular signal-regulated kinase (Erk) pathways. Imatinib mesylate (STI571) can inhibit c-kit tyrosine kinase activity, but clinical trials have resulted in failure. We investigated the possibility of SCF/c-kit-targeted therapy against SCLC. Using c-kit-positive SCLC cells (H209 and H69 cells) and SCF as a model of the autocrine mechanisms, the effects of SCF, LY294002, PD98059 or STI571 on Akt and Erk were assessed by Western blot analysis. The cell growth inhibitions of cisplatin, etoposide irinotecan and amrubicin (AMR) with or without SCF, LY294002, PD98059 or STI571 were evaluated by MTT assay. Treatment with SCF activated Akt and Erk and the activations were inhibited by STI571 in H209 but not in H69 cells. LY294002 and PD98059 inhibited SCF-induced Akt and Erk activation in H209 cells, respectively. STI571 alone did not exert growth inhibition in the SCF-treated cells. In H209 cells, SCF decreased the cytotoxicity of AMR, but not of other drugs. In H69 cells, SCF did not affect sensitivity to any drugs. LY294002 but not PD98059 restored or enhanced AMR-sensitivity in SCF-treated H209 or untreated H69 cells, respectively. STI571 restored the AMR-sensitivity of SCF-treated H209 cells to the basal level. If the SCF/c-kit contributes to Akt activation in vivo, the combination of STI571 and AMR may be effective against SCLC. Additionally, using a combination of AKT inhibitors and AMR may be a promising treatment in the future.
Authors:
Hisashi Suyama; Tadashi Igishi; Yasuto Ueda; Yasushi Shigeoka; Masahiro Kodani; Masato Morita; Kenichi Takeda; Takashi Sumikawa; Hirofumi Nakazaki; Keiji Matsunami; Shingo Matsumoto; Eiji Shimizu
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Oncology reports     Volume:  23     ISSN:  1791-2431     ISO Abbreviation:  Oncol. Rep.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2009-12-03     Completed Date:  2010-03-19     Revised Date:  2012-06-22    
Medline Journal Info:
Nlm Unique ID:  9422756     Medline TA:  Oncol Rep     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  217-22     Citation Subset:  IM    
Affiliation:
Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Japan.
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MeSH Terms
Descriptor/Qualifier:
Anthracyclines / pharmacology*
Cell Line, Tumor
Cell Survival
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors / pharmacology
Humans
Lung Neoplasms / drug therapy*,  metabolism*
Phosphatidylinositol 3-Kinases / metabolism*
Piperazines / pharmacology*
Proto-Oncogene Proteins c-akt / metabolism*
Pyrimidines / pharmacology*
Small Cell Lung Carcinoma / drug therapy*,  metabolism*
Tetrazolium Salts / pharmacology
Thiazoles / pharmacology
Chemical
Reg. No./Substance:
0/Anthracyclines; 0/Enzyme Inhibitors; 0/Piperazines; 0/Pyrimidines; 0/Tetrazolium Salts; 0/Thiazoles; 0/amrubicin; 152459-95-5/imatinib; 298-93-1/thiazolyl blue; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/AKT1 protein, human; EC 2.7.11.1/Proto-Oncogene Proteins c-akt

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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