Document Detail

Effects of MEK1 and PI3K inhibitors on allyl-, benzyl- and phenylethyl-isothiocyanate-induced G2/M arrest and cell death in Caco-2 cells.
MedLine Citation:
PMID:  16211242     Owner:  NLM     Status:  MEDLINE    
Isothiocyanates (ITCs) are potentially important cancer chemopreventive compounds found in cruciferous vegetables. In this study, three ITCs: allyl ITC, benzyl ITC and phenylethyl ITC, induced DNA cell-cycle changes and cell death in undifferentiated Caco-2 cells and their roles in PI3K/Akt and MEK/ERK signaling pathways have been investigated. Flow cytometric analysis was used to measure cell-cycle distribution, expression of mitotic marker (phosphorylated H3 histone), mitochondrial transmembrane potential for the determination of ITC-induced apoptosis measured by Annexin V-FITC staining and metabolic conversion of fluorescein diacetate, and quantification of sub-G1 population. Cellular MAPK and phosphorylated MAPK were measured using western blot analysis. All ITCs tested induced G2/M cell-cycle arrest after 24-h treatment, a time- and concentration-dependent activation of ERK1/2, dissipation of mitochondrial transmembrane potential and apoptosis. Both PI3K/Akt and MEK/ERK inhibitors, LY294002 and PD98059, attenuated the extent of BITC-induced cell death. Pretreatment of cells with either the PD98059 or LY294002 inhibitor, caused a dose-dependent inhibition of histone H3 (p-H3) phosphorylation. Despite the LY294002 inhibitor having no effect on the proportion of ITC-induced G2/M arrested cells, a significant decrease of p-H3/(G2/M) ratio in both PD98059- and LY294002-treated cells was observed. We suggest that the decrease of mitotic cells was compensated for by an increase of cells in G2 phase. LY294002 and PD98059 affect cell transition from G2 to M phase and from S to G2 phase respectively. These results indicate that isothiocyanates can induce cell cycle-change through multiple signaling pathways and more detailed study is merited to further unravel the chemopreventive and chemotherapeutic mechanisms of ITCs.
Jana Jakubíková; Ján Sedlák; James Bacon; Andrew Goldson; Yongping Bao
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of oncology     Volume:  27     ISSN:  1019-6439     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2005 Nov 
Date Detail:
Created Date:  2005-10-07     Completed Date:  2005-12-15     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  1449-58     Citation Subset:  IM    
Nutrition Division, Institute of Food Research, Norwich Research Park, Norwich NR4 7UA, UK.
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MeSH Terms
Apoptosis / drug effects
Caco-2 Cells
Cell Cycle / drug effects*
Cell Death / drug effects*
Chromones / pharmacology
Enzyme Inhibitors / pharmacology
Flavonoids / pharmacology
Flow Cytometry
Isothiocyanates / pharmacology*
MAP Kinase Kinase 1 / antagonists & inhibitors
Morpholines / pharmacology
Phosphatidylinositol 3-Kinases / antagonists & inhibitors
Signal Transduction / drug effects
Reg. No./Substance:
0/2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; 0/Chromones; 0/Enzyme Inhibitors; 0/Flavonoids; 0/Isothiocyanates; 0/Morpholines; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; EC 2.7.1.-/MAP2K1 protein, human; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Kinase Kinase 1

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

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