Article (Scientific journals)
Stimulation of topoisomerase II-mediated DNA cleavage by three DNA-intercalating plant alkaloids: cryptolepine, matadine, and serpentine.
Dassonneville, L.; Bonjean, Karine; De Pauw-Gillet, Marie-Claire et al.
1999In Biochemistry, 38 (24), p. 7719-26
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Keywords :
Alkaloids/chemistry/metabolism/pharmacology; Antineoplastic Agents, Phytogenic/pharmacology; Binding Sites/drug effects; Cell Death/drug effects; DNA/chemistry/drug effects/metabolism; DNA Topoisomerases, Type II/antagonists & inhibitors/chemistry/metabolism; Electrochemistry; Enzyme Inhibitors/pharmacology; Fluorescence Polarization; HL-60 Cells; Humans; Indole Alkaloids; Indoles; Intercalating Agents/chemistry/metabolism/pharmacology; Quinolines; Cryptolepine; Matadine; Serpentine
Abstract :
[en] Cryptolepine, matadine, and serpentine are three indoloquinoline alkaloids isolated from the roots of African plants: Cryptolepis sanguinolenta, Strychnos gossweileri, and Rauwolfia serpentina, respectively. For a long time, these alkaloids have been used in African folk medicine in the form of plant extracts for the treatment of multiple diseases, in particular as antimalarial drugs. To date, the molecular basis for their diverse biological effects remains poorly understood. To elucidate their mechanism of action, we studied their interaction with DNA and their effects on topoisomerase II. The strength and mode of binding to DNA of the three alkaloids were investigated by spectroscopy. The alkaloids bind tightly to DNA and behave as typical intercalating agents. All three compounds stabilize the topoisomerase II-DNA covalent complex and stimulate the cutting of DNA by topoisomerase II. The poisoning effect is more pronounced with cryptolepine than with matadine and serpentine, but none of the drugs exhibit a preference for cutting at a specific base. Cryptolepine which binds 10-fold more tightly to DNA than the two related alkaloids proves to be much more cytotoxic toward B16 melanoma cells than matadine and serpentine. The cellular consequences of the inhibition of topoisomerase II by cryptolepine were investigated using the HL60 leukemia cell line. The flow cytometry analysis shows that the drug alters the cell cycle distribution, but no sign of drug-induced apoptosis was detected when evaluating the internucleosomal fragmentation of DNA in cells. Cryptolepine-treated cells probably die via necrosis rather than via apoptosis. The results provide evidence that DNA and topoisomerase II are the primary targets of cryptolepine, matadine, and serpentine.
Disciplines :
Anatomy (cytology, histology, embryology...) & physiology
Pharmacy, pharmacology & toxicology
Author, co-author :
Dassonneville, L.
Bonjean, Karine ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie - Cytologie - Département des sciences biomédicales et précliniques
De Pauw-Gillet, Marie-Claire ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie - Cytologie - Département des sciences biomédicales et précliniques
Colson, Pierre ;  Université de Liège - ULiège > Département de chimie (sciences) > Département de chimie (sciences)
Houssier, Claude ;  Université de Liège - ULiège > Services généraux (Faculté des sciences) > Relations académiques et scientifiques (Sciences)
Quetin-Leclercq, Joëlle 
Angenot, Luc  ;  Université de Liège - ULiège > Département de pharmacie > Pharmacognosie
Bailly, Claude
Language :
English
Title :
Stimulation of topoisomerase II-mediated DNA cleavage by three DNA-intercalating plant alkaloids: cryptolepine, matadine, and serpentine.
Publication date :
1999
Journal title :
Biochemistry
ISSN :
0006-2960
eISSN :
1520-4995
Publisher :
American Chemical Society, Washington, United States - District of Columbia
Volume :
38
Issue :
24
Pages :
7719-26
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 25 May 2010

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