title: Binding to DNA and cytotoxic evaluation of ascididemin, the major alkaloid from the Mediterranean ascidian Cystodytes dellechiajei.
abstract: The isolation of ascididemin from the Mediterranean ascidian Cystodytes dellechiajei is described. This alkaloid consists of a planar pentacyclic chromophore which was investigated for its DNA-binding and cytotoxic properties. Spectroscopic measurements provided evidence that the drug intercalates into DNA. DNase I footprinting assays indicated that the binding of ascididemin to GC-rich sequences is favoured over binding to AT-rich and mixed sequences. Chemical probes were used to detect ligand-induced structural changes in DNA. The alkaloid induces a hyper-reactivity of the DNA towards potassium permanganate, but not towards diethylpyrocarbonate, just as is the case with ethidium bromide; it has little effect on the catalytic activities of topoisomerases I and II. Ascididemin exhibits marked cytotoxicity towards human leukaemic cells in vitro and appears to be practically equally toxic for drug-sensitive and multidrug-resistant cell lines. The results suggest that DNA, but not topoisomerases, may represent the critical cellular target at which this marine alkaloid exhibits its potent cytotoxic properties in vitro.
authors.affiliation: G.E.M.M.I.B., Université de Perpignan, France.
authors.forename: I
authors.initials: I
authors.lastname: Bonnard
authors.forename: N
authors.initials: N
authors.lastname: Bontemps
authors.forename: S
authors.initials: S
authors.lastname: Lahmy
authors.forename: B
authors.initials: B
authors.lastname: Banaigs
authors.forename: G
authors.initials: G
authors.lastname: Combaut
authors.forename: C
authors.initials: C
authors.lastname: Francisco
authors.forename: P
authors.initials: P
authors.lastname: Colson
authors.forename: C
authors.initials: C
authors.lastname: Houssier
authors.forename: M J
authors.initials: MJ
authors.lastname: Waring
authors.forename: C
authors.initials: C
authors.lastname: Bailly
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy; D008214:Lymphocytes / Q000187:drug effects; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014561:Urochordata / Q000737:chemistry*
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA