Reference : The DNA intercalating alkaloid cryptolepine interferes with topoisomerase II and inhibit...
Scientific journals : Article
Human health sciences : Pharmacy, pharmacology & toxicology
Life sciences : Anatomy (cytology, histology, embryology...) & physiology
http://hdl.handle.net/2268/39293
The DNA intercalating alkaloid cryptolepine interferes with topoisomerase II and inhibits primarily DNA synthesis in B16 melanoma cells.
English
Bonjean, K. [> > > >]
De Pauw, Marie-Claire mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Histologie - Cytologie - Département des sciences biomédicales et précliniques >]
Defresne, Marie-Paule mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Histologie - Cytologie >]
Colson, Pierre mailto [Université de Liège - ULg > Département de chimie (sciences) > Département de chimie (sciences) >]
Houssier, Claude mailto [Université de Liège - ULg > Services généraux (Faculté des sciences) > Relations académiques et scientifiques (Sciences) >]
Dassonneville, L. [> > > >]
Bailly, Claude [Université de Liège - ULg]
Greimers, Roland mailto [Centre Hospitalier Universitaire de Liège - CHU > > Anatomie pathologique >]
Wright, C. [> > > >]
Quetin-Leclercq, J. [> > > >]
Tits, Monique mailto [Université de Liège - ULg > Département de pharmacie > Phytochimie et phytothérapie >]
Angenot, Luc mailto [Université de Liège - ULg > Département de pharmacie > Pharmacognosie >]
1998
Biochemistry
American Chemical Society
37
15
5136-46
Yes
International
0006-2960
1520-4995
Washington
DC
[en] Alkaloids/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Base Sequence ; DNA Footprinting ; DNA Topoisomerases, Type II/antagonists & inhibitors ; DNA, Neoplasm/drug effects ; Dose-Response Relationship, Drug ; Indole Alkaloids ; Indoles ; Intercalating Agents/pharmacology ; Melanoma, Experimental/metabolism ; Mice ; Molecular Sequence Data ; Nucleic Acid Denaturation/drug effects ; Quinolines ; Spectrum Analysis
[en] Cryptolepine hydrochloride is an indoloquinoline alkaloid isolated from the roots of Cryptolepis sanguinolenta. It is characterized by a multiplicity of host-mediated biological activities, including antibacterial, antiviral, and antimalarial properties. To date, the molecular basis for its diverse biological effects remains largely uncertain. Several lines of evidence strongly suggest that DNA might correspond to its principal cellular target. Consequently, we studied the strength and mode of binding to DNA of cryptolepine by means of absorption, fluorescence, circular, and linear dichroism, as well as by a relaxation assay using DNA topoisomerases. The results of various optical and gel electrophoresis techniques converge to reveal that the alkaloid binds tightly to DNA and behaves as a typical intercalating agent. In DNAase I footprinting experiments it was found that the drug interacts preferentially with GC-rich sequences and discriminates against homo-oligomeric runs of A and T. This study has also led to the discovery that cryptolepine is a potent topoisomerase II inhibitor and a promising antitumor agent. It stabilizes topoisomerase II-DNA covalent complexes and stimulates the cutting of DNA at a subset of preexisting topoisomerase II cleavage sites. Taking advantage of the fluorescence of the indoloquinoline chromophore, fluorescence microscopy was used to map cellular uptake of the drug. Cryptolepine easily crosses the cell membranes and accumulates selectively into the nuclei rather than in the cytoplasm of B16 melanoma cells. Quantitative analyses of DNA in cells after Feulgen reaction and image cytometry reveal that the drug blocks the cell cycle in G2/M phases. It is also shown that the alkaloid is more potent at inhibiting DNA synthesis rather than RNA and protein synthesis. Altogether, the results provide direct evidence that DNA is the primary target of cryptolepine and suggest that this alkaloid is a valid candidate for the development of tumor active compounds.
http://hdl.handle.net/2268/39293
10.1021/bi972927q

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