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.
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.
Devy
Jérôme
J
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
Ouchani
Farid
F
Oudot
Christelle
C
Helesbeux
Jean Jacques
JJ
Vanquelef
Enguerran
E
Salesse
Stéphanie
S
Rabenoelina
Fanja
F
Al-Khara
Siana
S
Letinois
Isabelle
I
Duval
Olivier
O
Martiny
Laurent
L
Charpentier
Emmanuelle
E
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D053119:Benzophenanthridines / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005341:Fibrinolysin / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007939:Leukemia L1210 / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D010960:Plasminogen Activators / Q000378:metabolism*
D000470:Alkaloids; D053119:Benzophenanthridines; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C568781:N-methyl-12-ethoxy-2-hydroxy-3,8,9-trimethoxybenzo(c)phenanthridinium; C002066:fagaronine; D007611:Aprotinin; D010960:Plasminogen Activators; D005341:Fibrinolysin; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D053511:Matrix Metalloproteinase 14