Low-molecular-weight dextran derivatives (f-CMDB) enter the nucleus and are better cell-growth inhibitors compared with parent CMDB polymers.
Carboxymethyldextrans-benzylamide (CMDB) are dextran derivatives that are statistically substituted with carboxymethyl and benzylamide groups. These molecules display a variety of biological effects, one of which is their inhibitory activity against mammary tumor cell growth, both in vitro and in vivo. We and others have previously shown that the effects of CMDB on cell growth are related to their ability to interact with the growth factor FGF-2. The binding modifies the conformation of FGF-2, leading to the suppression of its mitogenic activity. Here, the method previously reported to fragment natural polysaccharide fucans has been applied to CMDB (80,000 g/mol). f-CMDB (fragmented CMDB) of molecular weights from 6000 to 20,000 g/mol were found to be more potent inhibitors of MCF7 mammary tumor cell growth than high-molecular-weight CMDB. Confocal microscopy experiments using CMDB and f-CMDB labeled with the fluorophore DTAF (5-([4,6-dichlorotriazine-2-yl]amino) fluorescein) indicate that only low-molecular-weight f-CMDB penetrate into the nucleus of MCF7 cells. It is thus assumed that the better inhibitory properties demonstrated by f-CMDB, compared with CMDB, are related to their better ability to penetrate the nucleus and interact with nuclear targets, including topoisomerase II. The DNA relaxation properties of the latter are inhibited in vitro by both CMDB and f-CMDB. These findings could help us to develop models of low-molecular-weight oligosaccharide derivatives exhibiting better antiproliferative and antitumor properties.
Bittoun
P
P
Département de Biologie Structurale, UMR 8532 CNRS, Institut Gustave-Roussy, Villejuif, France.
Avramoglou
T
T
Vassy
J
J
Crépin
M
M
Chaubet
F
F
Fermandjian
S
S
D002384:Catalysis; D002455:Cell Division / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D003911:Dextrans / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D008970:Molecular Weight; D011108:Polymers; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D003911:Dextrans; D011108:Polymers; D059005:Topoisomerase II Inhibitors; C014392:carboxymethyl dextran; D004250:DNA Topoisomerases, Type II