Document Detail


The anti-invasive activity of synthetic alkaloid ethoxyfagaronine on L1210 leukemia cells is mediated by down-regulation of plasminogen activators and MT1-MMP expression and activity.
MedLine Citation:
PMID:  20349265     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Quaternary benzo[c]phenanthridines such as fagaronine are natural substances which have been reported to exhibit anticancer and anti-leukemic properties. However, the therapeutic use of these molecules is limited due to the high dose required to exhibit anti-tumor activity and subsequent toxicity. In this study, we describe the therapeutic potential of a new derivative of fagaronine, Ethoxyfagaronine (N-methyl-12-ethoxy-2hydroxy-3, 8, 9-trimethoxybenzo[c]-phenanthridiniumchlorhydrate) as an anti-leukemic agent. Cytotoxic activity and cell growth inhibition of Ethoxyfagaronine (Etxfag) was tested on murine L1210 leukemia cells using trypan blue assay and MTT assay. At the concentration of 10(-7) M, Etxfag induced less than 10% of cell death. Etxfag (10(-7) M) was tested on L1210 cell invasiveness using matrigel™ precoated transwell chambers and efficiently reduces the invasive potential of L1210 cells by more than 50% as compared with untreated cells. Western blot and immunofluorescence experiments showed that Etxfag decreased both MT1-MMP expression and activation at the cell surface, decreased plasmin activity by down-regulating u-PAR and uPA expression at the cell surface and increasing PAI-1 secretion in conditioned media. The set of our findings underscore the therapeutic potential of ethoxyfagaronine as a new potential anticancer agent able to prevent leukemic cell dissemination.
Authors:
Jérôme Devy; Farid Ouchani; Christelle Oudot; Jean Jacques Helesbeux; Enguerran Vanquelef; Stéphanie Salesse; Fanja Rabenoelina; Siana Al-Khara; Isabelle Letinois; Olivier Duval; Laurent Martiny; Emmanuelle Charpentier
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-28
Journal Detail:
Title:  Investigational new drugs     Volume:  29     ISSN:  1573-0646     ISO Abbreviation:  Invest New Drugs     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-08-24     Completed Date:  2012-01-24     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  8309330     Medline TA:  Invest New Drugs     Country:  United States    
Other Details:
Languages:  eng     Pagination:  730-41     Citation Subset:  IM    
Affiliation:
UMR CNRS 6237, Laboratoire SiRMa, IFR 53 Interactions Cellules Microenvironnement, UFR Sciences Exactes et Naturelles, Moulin de la Housse, Université de Reims Champagne Ardenne, BP 1039, F-51687 Reims Cedex 2, France. jerome.devy@univ-reims.fr
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MeSH Terms
Descriptor/Qualifier:
Alkaloids / pharmacology*
Animals
Aprotinin / pharmacology
Benzophenanthridines / pharmacology*
Cell Death / drug effects
Cell Proliferation / drug effects
Dipeptides / pharmacology
Down-Regulation / drug effects*
Enzyme Activation / drug effects
Fibrinolysin / metabolism
Gelatinases / metabolism
Gene Expression Regulation, Enzymologic / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Leukemia L1210 / enzymology*,  genetics,  pathology*
Matrix Metalloproteinase 14 / genetics,  metabolism*
Matrix Metalloproteinase 2 / genetics,  metabolism
Matrix Metalloproteinase 9 / genetics,  metabolism
Mice
Neoplasm Invasiveness
Plasminogen Activators / metabolism*
Chemical
Reg. No./Substance:
0/Alkaloids; 0/Benzophenanthridines; 0/Dipeptides; 0/N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; 0/N-methyl-12-ethoxy-2-hydroxy-3,8,9-trimethoxybenzo(c)phenanthridinium; 41758-44-5/fagaronine; 9087-70-1/Aprotinin; EC 3.4.21.-/Plasminogen Activators; EC 3.4.21.7/Fibrinolysin; EC 3.4.24.-/Gelatinases; EC 3.4.24.-/Mmp9 protein, mouse; EC 3.4.24.24/Matrix Metalloproteinase 2; EC 3.4.24.24/Mmp2 protein, mouse; EC 3.4.24.35/Matrix Metalloproteinase 9; EC 3.4.24.80/Matrix Metalloproteinase 14

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